Riluzole Series. Synthesis and in Vivo - American Chemical Society

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J. Med. Chem. 1999, 42, 2828-2843

Riluzole Series. Synthesis and in Vivo “Antiglutamate” Activity of 6-Substituted-2-benzothiazolamines and 3-Substituted-2-imino-benzothiazolines Patrick Jimonet,* Franc¸ ois Audiau, Michel Barreau, Jean-Charles Blanchard, Alain Boireau, Yvette Bour, Marie-Annick Cole´no, Adam Doble, Gilles Doerflinger, Claudine Do Huu, Marie-He´le`ne Donat, Jean Marie Duchesne, Pierre Ganil, Claude Gue´re´my, Eliane Honore´, Bernard Just, Roselyne Kerphirique, Sylvie Gontier, Philippe Hubert, Pierre M. Laduron, Joseph Le Blevec, Mireille Meunier, Jean-Marie Miquet, Conception Nemecek, Martine Pasquet, Odile Piot, Jeremy Pratt, Jean Rataud, Michel Reibaud, Jean-Marie Stutzmann, and Serge Mignani Rhoˆ ne-Poulenc S.A., Rhoˆ ne-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, 13 quai Jules Guesde, B.P. 14, F 94403 Vitry-sur-Seine Cedex, France Received April 1, 1998

Two series of analogues of riluzole, a blocker of excitatory amino acid mediated neurotransmission, have been synthesized: monosubstituted 2-benzothiazolamines and 3-substituted derivatives. Of all the compounds prepared in the first series, only 2-benzothiazolamines bearing alkyl, polyfluoroalkyl, or polyfluoroalkoxy substituents in the 6-position showed potent anticonvulsant activity against administration of glutamic acid in rats. The most active compounds displaying in vivo “antiglutamate” activity were the 6-OCF3 (riluzole), 6-OCF2CF3, 6-CF3, and 6-CF2CF3 substituted derivatives with ED50 values between 2.5 and 3.2 mg/kg i.p. Among the second series of variously substituted benzothiazolines, compounds as active as riluzole or up to 3 times more potent were identified in two series: benzothiazolines bearing a β-dialkylaminoethyl moiety and compounds with an alkylthioalkyl chain and their corresponding sulfoxides and sulfones. The most potent derivatives were 2-imino-3-(2-methylthio)- and 2-imino-3-(2-methylsulfinyl)-ethyl-6-trifluoromethoxybenzothiazolines (61 and 64, ED50 ) 1.0 and 1.1 mg/kg i.p., respectively). In addition, intraperitoneal administration of some of the best benzothiazolines protected mice from mortality produced by hypobaric hypoxia. Introduction In the 1950s, a number of 2-benzothiazolamines were intensively studied as central muscle relaxants. The major work concerned with this field is that of Domino et al. 1 Since then medicinal chemists have not taken an active interest in this chemical family. Biologists’ attention was drawn to this series when the pharmacological profile of riluzole was discovered. Riluzole (1, 6-(trifluoromethoxy)-2-benzothiazolamine, PK 26124, RP 54274, Rilutek) was found to interfere with glutamate neurotransmission in biochemical, electrophysiological, and behavioral experiments.

In biochemical models riluzole antagonized the release of acetylcholine induced by N-methyl-D-aspartate (NMDA) in vitro and blocked the increase in cyclic guanosine monophosphate levels in the cerebellar cortex induced by glutamate in vitro and in vivo.2 Riluzole was also found to be a potent antagonist of glutamatestimulated release of D-aspartate in rodent cerebellar cells,3,4 and it decreased the glutamate-induced release of dopamine (DA) in the “push-pull” model in the cat striatum.5 In addition, electrophysiological studies have shown riluzole to be active against responses evoked by mi* To whom correspondence should be addressed.

croiontophoretically applied excitatory amino acids in motoneurons of the facial nucleus.6 Thus riluzole seems to interfere with glutamatergic transmission at both the pre- and postsynaptic level. However, riluzole did not act as a competitive antagonist at NMDA type receptors,7 and it had negligible activity on 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid binding, a selective NMDA antagonist.8 Furthermore, it did not interact, at least at submillimolar concentrations, with kainate (KA) and quisqualate (QUIS) sensitive subtypes of excitatory amino acid receptor.9 Finally it has also been demonstrated that riluzole is a highly specific blocker of inactivated Na channels,10 which in turn inhibit glutamate release. In pharmacological experiments, riluzole possessed anticonvulsant properties in different models including maximal electroshock in mice, convulsions induced by glutamic acid decarboxylase inhibitors in mice and rats, sound-induced convulsions in DBA/2 mice, and photosensitive epilepsy in baboons. However, unlike benzodiazepines, valproic acid, or barbiturates, riluzole was ineffective against seizures induced by pentylenetetrazole, bicuculline, or picrotoxin11 and did not induce phencyclidine-like behavioral activity in pigeons, rats, or monkeys.12 Riluzole has been shown to have interesting neuroprotective effects in vitro, protecting primary cultures of rat cortical neurones against anoxic stress13 and against an excitotoxic factor present in cerebrospinal fluid from ALS patients.14 Furthermore, rat motoneurons were protected by riluzole from the excitotoxic effects of glutamic acid uptake inhibitors.15 These stud-

10.1021/jm980202u CCC: $18.00 © 1999 American Chemical Society Published on Web 07/02/1999

Riluzole Series

Journal of Medicinal Chemistry, 1999, Vol. 42, No. 15

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Table 1. Physical Properties and “Antiglutamate” Activity of 6-Substituted-2-benzothiazolamines

no.

R

method

formulaa

mp,°C

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 (() MK-801

OCF3 H F Cl Br I NH2 CN CO2Et NO2 SO2Me OMe O-t-C4H9 SiMe3 C6H11 Ph Me Et n-Pr i-Pr n-Bu t-Bu n-Pen t-Pen CH2CMe3 n-Hex n-Hep CH2CF3 COCF3 SCF3 OCHF2 OCH2CF3 OCH2C2F5 OCF2CHF2 OC2F5 C2F5 CF3

A Ew A E A B

C8H5F3N2OS C7H6N2S C7H5FN2S C7H5ClN2S C7H5BrN2S C7H5IN2S C7H7N3S C8H5N3S C10H10N2O2S C7H5N3O2S C8H8N2O2S2 C8H8N2OS C11H14N2OS C10H14N2SSi C13H16N2S C13H10N2S C8H8N2S C9H10N2S C10H12N2S C10H12N2S C11H14N2S C11H14N2S C12H16N2S C12H16N2S C12H16N2S C13H18N2S C14H20N2S C9H7F3N2S C9H5F3N2OS C8H5F3N2S2 C8H6F2N2OS C9H7F3N2OSr C10H7F5N2OS C9H6F4N2OS C9H5F5N2OS C9H5F5N2S,HCl C8H5F5F3S

119s

EtOH-H2O

184b 209c

EtOH e

214e 208f 207g 243h

acetone MeCN d EtOH-H2O

224i 147j 183 140 217k 248l 137m 115n 119o 125p 114q 146 122 134 196 121 109 186 249 155r 118t 134 147 161 156 191 122u

PrOH EtOH-H2O CHCl3-hexane d MeCN CHCl3-EtOAc-EtOH d cyclohexane cyclohexane cyclohexane EtOAc-cyclohexane cyclohexane cyclohexane d d cyclohexane cyclohexane d EtOAc i-Pr2O/cyclohexane toluene d toluene toluene cyclohexane EtOH-acetone cyclohexane

A A E B B A D A A A A A A A A A A A A A A A A A A A A A A A

cryst. solvent

ClogP34 3.41 2.00 2.15 2.72

4.58 2.50 3.03 3.56 3.43 4.09 3.83 4.62 4.36 5.14 5.67 4.03 2.74 6.50 4.16 5.15 3.26 2.96

protection against glutamic acid evoked convulsions ED50, mg/kg i.p.v 3.2 >10 >10 >10 >10 >10 >10 >10 >10 10 >10 >10 >10 5 >10 >10 >10 7 6 >10 4 4 7.5 >10 >10 7 >10 8 >10 8 7.5 6.5 7.5 8.5 2.5 2.5 2.5 2.2

a Microanalysis results on new compounds were within (0.4% of theoretical values unless otherwise indicated. b Lit.39 mp 182 °C. Lit.40 mp 210 °C. d Purified on a silica gel column and triturated in 40/60 petroleum ether. e Lit.41 mp 217 °C. f Lit.42 mp 207 °C. g Lit.19 mp 198 °C. h Lit.43 mp 242 °C. i Lit.44 mp 224-6 °C. j Lit.43 mp 147 °C. k Lit.52 mp 219-21 °C. l Lit.45 mp 227-8 °C. m Lit.19 mp 136 °C. n Lit.41 mp 116 °C. o Lit.46 mp not indicated. p Lit.47 mp 123-6 °C. q Lit.48 mp not indicated. r Lit.49 mp 153-4 °C. s Lit.50 mp 117-9 °C. t Lit.51 mp 116 °C. u N: calcd, 11.29; found, 10.8. v The variability in the glutamic acid-induced convulsion test is between 15 and 25%. w Method E: commercially available product (Aldrich). c

ies suggest that riluzole may have neuroprotective effects in whole animals, and this has indeed been demonstrated in animal models of cerebral ischemia.16,17 Clinical studies have also demonstrated that riluzole slows disease progression in amyotrophic lateral sclerosis.18 In this paper, we describe the synthesis of many close analogues of riluzole, thus showing the crucial importance of the 6-substituent of these benzothiazoles, and the preparation of 3-substituted derivatives of riluzole and their in vivo “antiglutamate” activity. All the compounds were evaluated, together with reference drugs, for their ability to protect against seizures induced by intracerebroventricular administration of glutamic acid in rats. Chemistry 6-Substituted-2-benzothiazolamines. 2-Benzothiazolamines 1-37 bearing various substituents in the 6-position are listed in Table 1. Scheme 1 shows the

Scheme 1

classical synthetic route19 used for the preparation of most of them: 1, 3, 5, 8, 9, 13, 15-37. One-pot reaction of the appropriate aniline with thiocyanogen generated from bromine and alkaline thiocyanate in acetic acid medium led to formation of the desired products in good to moderate yields (method A). The starting anilines have been described in the literature, except 4-(2,2,2trifluoroethyl)aniline which was prepared by reduction of the corresponding nitro compound. Another classical way20 previously used for the preparation of 2-benzothiazolamines is cyclization of phenylthioureas with bromine in chloroform (Scheme 2, method B): compounds 6, 11, and 12 were thus prepared.

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Table 2. Physical Properties and “Antiglutamate” Activity of Trifluoromethoxy-2-benzothiazolamines

no

OCF3 position

method

formulaa

mp,°C

cryst. solvent

protection against glutamic acid-evoked convulsions ED50, mg/kg i.p.c

1 38 39 40

6 4 5 7

A B B C

C8H5F3N2OS C8H5F3N2OS C8H5F3N2OS,HCl C8H5F3N2OS b

119 132 158 108

EtOH-H2O CCl4 d e

3.2 >10 >10 >10

a Microanalysis results were within (0.4% of theoretical values unless otherwise indicated. b Determined for C, H, N. c The variability in the glutamic acid-induced convulsion test is between 15 and 25%. d Washed with acetone. e Purified on a silica gel column.

Scheme 2

Scheme 3

Table 3. 3-Substituted-2-imino-6-trifluoromethoxy-benzothiazolines

Compounds 2, 4, and 10 are commercially available and 7 was obtained through reduction of the corresponding nitro compound 10. Positional isomers of riluzole were synthesized as outlined in Scheme 2 according to method B and are listed in Table 2. Two isomers, 38 and 39, with the trifluoromethoxy group at the 4- or 5-position were obtained from the corresponding ortho or meta thioureas. Cyclization of this last thiourea did not give the 7-trifluoromethoxylated isomer 40; it only gave the 5-trifluoromethoxylated isomer 39. Synthesis of 40 was achieved via a five-step procedure (Scheme 2, method C): Nitration of 2-trifluoromethoxyacetanilide with nitronium tetrafluoroborate afforded a mixture of mononitrated products which, after separation and hydrolysis, yielded the 2-nitroaniline isomer; this compound was treated with amyl nitrite and iodine to give the corresponding 2-iodonitro derivative. After reduction, the resulting 2-iodoaniline was finally cyclized into 40 by using thiourea and Ni(Et3P)421 generated in situ from bis(triethylphosphine)nickel(II) chloride and sodium cyanoborohydride as a reducing agent. The trimethylsilyl derivative, 14, was prepared as

no

R

1 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58

H (riluzole) methyl ethyl n-propyl n-butyl allyl propargyl CH2CN CH2Ph (CH2)2Ph CH2CO2Me CH2CO2H CH2CONH2 CH2CONEt2 (CH2)2SO2NH2 (CH2)2SO2NHMe (CH2)2SO2NMe2 (CH2)2SO3H (CH2)2OH

method F F F F F F F F F F F F I I I I F

protection against glutamic acid-evoked convulsions ED50, mg/kg i.p.a 3.2 5.0 5.0 4.5 10 7.0 4.0 3.5 >10 >10 >10 >10 7.0 9.0 6.0 4.0 >10 >10 8.0

a The variability in the glutamic acid-induced convulsion test is between 15 and 25%.

shown in Scheme 3 (method D). The bromo compound 5 was treated with n-butyllithium and chlorotrimethylsilane to give after hydrolyses the desired product, 14, in a low but not optimized yield. 3-Substituted-2-imino-benzothiazolines. Compounds listed in Tables 3-6 were synthesized by the routes outlined in Scheme 4. Alkylation of 6-trifluoromethoxy-2-benzothiazolamine 1 occurred exclusively on the endocyclic nitrogen, at the 3-position. 22 The reaction was carried out very easily by mixing 1 and the alkylating agent R-X in an alcohol, methylethyl ketone, or dimethylformamide and refluxing the mixture for several hours (method F). In many experiments, salts of the expected products precipitated. The simplic-

Riluzole Series


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Scheme 4a

a Reagents: (a) RX, EtOH or MEK or DMF, reflux; (b) Br(CH ) OH, EtOH, reflux; (c) TosCl, pyridine, 0 °C-rt, (d) CF CO Et, Et N, 2 n 3 2 3 EtOH, rt; (e) R1R2NH2, NaHCO3, DMF, 80 °C or R′SNa, DMF; (f) aqueous K2CO3, MeOH, rt; (g) Br(CH2)2OH, 160 °C; (h) TosCl, Et3N, CH2Cl2, 0 °C-rt; (i) R1R2NH, NaHCO3, DMF, 80 °C; (j) HCl, aqueous AcOH, reflux; (k) Br2, KSCN, AcOH, rt; (l) CH2dCHSO2F, DMF, rt; (m) R1R2NH, acetone, reflux or AcOH, reflux; (n) aqueous HCl or HBr, reflux; (o) VOC-Cl, DBU, CH2Cl2, rt, then aqueous HCl, MeOH, reflux; (p) 1 equiv mCPBA, EtOH, -35 °C (m ) 1) or 2 equiv mCPBA, CH2Cl2, rt (m ) 2).

Table 4. Sulfur-Containing 3-Substituted Benzothiazolines

S(O)m-R no.

R

m

n

method

59 60 61 62 63 64 65 66 67 68 69 70 71

Me Me Me Et Pr Me Me H Ph Ph Me Me Me

0 1 0 0 0 1 2 0 0 1 0 1 2

1 1 2 2 2 2 2 2 2 2 3 3 3

F F F F

F G

protection against glutamic acid-evoked convulsions ED50, mg/kg i.p.a 3.0 2.3 1.0 2.2 2.4 1.1 1.8 2.0 4.5 4.2 4.2 2.3 5.0


ity of this reaction and the availability of many potential alkylating reagents allowed a rapid synthesis of a large number of compounds: 41-50, 52, 53, 58, 59, 61-63, 67, 73-75. Yields were moderate or low, except for molecules containing a thioether group on the side chain, due to β-halosulfide reagent activation via an electrophilic episulfonium.23 In some cases, especially

when the required alkylating agents R-X were not commercially available, alternative methods were used. According to method G, riluzole reacted with an appropriate hydroxyalkyl bromide to give 58 or 96.24 When treated by p-toluenesulfonyl chloride, the alcohol 58 did not give the corresponding tosylate since, predictably, intramolecular nucleophilic attack of the imino group occurred, leading to the tricyclic derivative 97. This cyclization also occurred spontaneously with acetyl, trityl, or t-Boc-imino protected compounds.25 To overcome this difficulty, imine nitrogen nucleophilicity was decreased by imine acylation with an electron-withdrawing group such as trifluoroacetyl (compounds 98 and 99); thus the tosylates 100 and 101 were isolated with a good yield and reacted with appropriate thiolate R′SNa or amines RlR2NH to give the expected compounds 69, 80, and 81. However, yields were still low (10-30%), except for 69 (83%). Method H avoided cyclization side reactions by reacting 2-bromoethanol with 4-trifluoromethoxy aniline.26 The resulting compound 102 was tosylated to give the ditosylate 103, which was then condensed with an appropriate amine RlR2NH to give 104-107 after acid hydrolyses. Ring closure to the benzothiazoline derivatives 76-79 was effected by thiocyanogen generated in situ from bromine and potassium thiocyanate in acetic acid medium.27 Overall yield remained low due to the nonoptimized thiazole ring formation step. Sulfonamides 54, 55, 56 and sulfonic acid 57 were synthesized according to method I. Michael addition of

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Jimonet et al.

Table 5. Nitrogen-Containing 3-Substituted Benzothiazolines

a

The variability in the glutamic acid-induced convulsion test is between 15 and 25%.

Table 6. Simultaneous Modifications in Positions 3 and 6

no.

R

Z

protection against glutamic acid-evoked convulsions ED50, mg/kg i.p.a

82 73 83 84 85 86 87 88 89

NMe2 NMe2 NMe2 S(O)Et S(O)Et S(O)Et S(O)Et S(O)2Et S(O)2Et

H OCF3 t-Bu t-Bu n-Bu OCF3 CF3 C2F5 OC2F5

>10 2.3 >10 >10 >10 1.2 1.7 2.1 2.6


4-trifluoromethoxyaniline to ethenesulfonyl fluoride easily gave 108,28 which was converted into either the expected benzothiazoline sulfonamides by reaction with appropriate amines or the sulfonic acid by hydrolysis in aqueous acetic acid, followed by the usual thiazole ring closure. Compounds 51 (R ) CH2CO2H) and 66 (R ) (CH2)2SH) could not be obtained directly from riluzole by reaction with the functionalized reagent; they were thus prepared in a two-step process after acidic hydrolyses

of their benzothiazoline precursors 50 (R ) CH2CO2Me) and 110 (R ) (CH2)2StBu), respectively. Vinylchloroformate (VOC-Cl) monodemethylation of the dimethylamino derivative 73 (R ) (CH2)2N(CH3)2 gave 72. 29 Sulfoxides (compounds 60, 64, 68, and 70) and sulfones (compounds 65 and 71) were prepared from their respective parent thioethers by oxidation with mchloroperbenzoic acid (mCPBA). Use of 1 equiv of mCPBA in ethanol at -35 °C afforded sulfoxides, whereas 2 equiv of mCPBA in dichloromethane at room temperature gave sulfones. The 6-substituted analogues of the most active benzothiazolines bearing amino- and sulfur-containing side chains are listed in Table 6; they were obtained following the same synthetic pathway (method F) as the trifluoromethoxylated compounds, a pathway starting from the corresponding benzothiazoles. The importance of the imino group of the thioether-containing compounds 61 and 62 was demonstrated by the synthesis of imino-modified benzothiazolines (Table 7, Schemes 5 and 6). Imino alkylated benzothiazolines 90 and 91 were obtained by direct alkylation of the N-2-alkylated benzothiazoles 113 and 114 with chloroethyl-methyl(or ethyl)-sulfide (Scheme 5). Acetylation of 61 provided 94. Reaction of the tricyclic key intermediate 116 with hydroxylamine and methoxylamine led, after alkylation of the free thiol, to oximes 92 and 93, respectively, whereas ring opening with sodium methoxide gave directly the 2-benzothiazolone 95 (Scheme 6).30 The

Riluzole Series


Table 7. Simultaneous Modifications in Positions 2 and 3

no.

R

X

protection against glutamic acid-evoked convulsions ED50, mg/kg i.p.a

62 90 91 92 93 94 95

SMe SEt SMe SEt SEt SMe SMe

NH NMe NEt NOMe NOH NCOMe O

2.2 3.7 8.5 >10 >10 >10 >10


Scheme 5a

a Reagents: (a) NH NH , (b) SOCl , (c) aqueous RNH , (d) 2 2 2 2 Cl(CH2)2SR′, MEK, reflux.

same reaction performed with sodium methyl sulfide did not lead to 2-benzothiazolethione, but unexpectedly stopped at a stable tricyclic benzothiazole derivative 119 (inactive in our tests), which contains a rarely observed four-heteroatom-substituted carbon atom. Results and Discussion Compounds 1-95 were evaluated for their ability to protect against seizures induced by intracerebroventricular administration of glutamic acid in rats31 (see Experimental Section). The in vivo “antiglutamate” activity of the studied compounds is listed in Tables 1-7. In this test, the noncompetitive NMDA receptor antagonist dizocilpine ((()MK-801, see Table 1) was found to be active with an ED50 of 2.2 mg/kg i.p. (administered 10 min before challenge). 6-Substituted-2-benzothiazolamines. In this test, riluzole 1 had an ED50 of 3.2 mg/kg i.p., whereas the unsubstituted 2-benzothiazolamine 2 was much less active. Many 6-substituted-2-benzothiazolamines such as compounds 7 (R ) NH2), 8 (R ) CN), 9 (R ) CO2C2H5), 10 (R ) NO2), 11 (R ) SO2CH3), 12 (R )

2833

OCH3), 13 (R ) O-t-C4H9), 16 (R ) C6H5), and 29 (R ) COCF3) displayed very weak activity (ED50 g 10 mg/kg i.p.). Thus electronic factors seem to be relatively unimportant, since substitution with electron-donating groups as well as electron-withdrawing groups at the 6-position did not increase the activity of the parent compound 2. Additional evidence for this trend comes from comparison of the activity for the 6-trifluoromethoxy derivative 1 with the 6-chloro derivative 4 (ED50 ) 3.2 mg/kg i.p. vs ED50 > 10 mg/kg i.p., respectively). It is known that the trifluoromethoxy group deactivates the benzene ring by inductive electron withdrawal and donates electrons by resonance exactly as does chlorine.32 Replacement of chlorine by such a “pseudohalogen” in compounds of medicinal interest has frequently resulted in active compounds; for example the 7-chloro substituent in diazepam was replaced by a trifluoromethoxy group with retention of activity.33 Thus it appears that riluzole’s in vivo activity depends essentially on nonelectronic factors such as lipophilicity. Examination of the structure of the most potent compounds in the series gave support to this hypothesis: all the significantly active compounds fell into two sets: (1) compounds bearing a rather large alkyl substituent and (2) compounds bearing a polyfluoroalkyl or a polyfluoroalkoxy substituent. (1) On varying the size of the alkyl moiety it appeared that there was an optimal size for activity. Among the linear alkyl substituted derivatives (compounds 17-19, 21, 23, 26, 27), the most potent is 21 (R ) C4H9). Lengthening or shortening the chain decreased the potency (C4H9 > C3H7 ∼ C2H5 > CH3 and C4H9 > C5H11 ∼ C6H13 > C7H15). Changing the butyl group (compound 21) to a tert-butyl group (compound 22) or a trimethylsilyl group (compound 14) did not affect the activity; on the other hand, decreasing the size of branched substituents (compound 20, R ) isopropyl) or increasing the size (compounds 24, R ) t-C5H11, 25, R ) CH2-t-C4H9) led to compounds with weak activity (ED50 > 10 mg/kg i.p.). (2) Compounds closely related to riluzole 1, 6-pentafluoroethoxy-2-benzothiazolamine 35 and perfluoroalkyl derivatives 36 and 37 displayed strong “antiglutamate” activities with ED50 values of 2.5 mg/kg i.p. Replacement of one or more fluorine atoms by hydrogens always decreased the activity (28 (R ) CH2CF3) < 36 (R ) C2F5); 31 (R ) OCHF2) < 1 (R ) OCF3); 34 (R ) OCF2CHF2) < 35 (R ) OC2F5)). All these results are consistent with lipophilicity of the substituent at the 6-position as a major contributing factor for “antiglutamate” activity. Calculated ClogP34 of compounds listed in Table 1 showed that values around 4.0 are the most favorable in the alkyl series, whereas a wider range is observed in the fluorinated series: 2.96 (compound 37)-5.15 (compound 35). Thus, in this latter series no clear-cut correlation can be made between ClogP and biological activity since in vivo testing involves not only drugreceptor interactions but also additional parameters such as bioavailability, metabolism, and brain penetration. In addition, the trifluoromethoxy group position on the aromatic ring was of crucial importance, since all positional isomers of riluzole (compounds 38-40) have ED50 values of >10 mg/kg i.p. (Table 2). From the in vivo data obtained in this study we can only speculate that the moiety in the 6-position in

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Jimonet et al.

Scheme 6a

a Reagents: (a) thiourea, 1 N H SO , 60 °C; (b) 1,2-dibromoethane, DMF; (c) NH OR, 1 N NaOH, refulx; (d) EtONa, EtOH, EtBr, rt; 2 4 2 (e) MeONa, MeOH, reflux; (f) MeSNa, EtOH, rt.

riluzole or in its active analogues is an essential anchorage point allowing lipophilic interactions at a binding site, but influence of other parameters such as bioavailability and/or other mechanisms of action cannot be ruled out. Study of this series of compounds in relevant in vitro tests would be required to corroborate this hypothesis and thereby to allow quantitative structure-activity relationship (QSAR) analysis of substituent effects. QSAR analysis of a set of substituted benzothiazoles has already been done using sodium flux measurements in rat cortical membranes as an in vitro test.35 Our conclusions are similar to those reached by Hays et al.: need for a small liphophilic substituent and emphasis on other probable mechanisms of action limiting QSAR interpretation and responsible for in vivo effects. 3-Substituted-2-imino-benzothiazolines. In contrast with the 2-methylamino-6-trifluoromethoxy-benzothiazole 113 which was inactive at 10 mg/kg i.p. (data not shown), the 3-methyl derivative 41 displayed a good anticonvulsant activity (ED50 ) 5 mg/kg i.p.). This encouraging result prompted us to study systematically the substituent influence at the 3-position (Table 3). Replacement of the methyl group by another aliphatic chain such as an ethyl, propyl, allyl, or propargyl group (compounds 42, 43, 45, and 46, respectively) did not substantially affect the activity, whereas introduction of larger alkyl substituents (e.g., butyl, compound 44) or aromatic substituents (compounds 48 and 49) reduced the potency dramatically. At this stage, we

prepared some functionalized benzothiazolines: ester (50), amides (52 and 53), sulfonamides (54-56), carboxylic acid (51), sulfonic acid (57), and alcohol (58) did not display more potency than riluzole, and no clearcut correlation between structure and activity can be deduced. A significantly enhanced “antiglutamate” activity was obtained by introduction of nitrogen- or sulfur-containing 3-substituents. Concerning the sulfur-containing series, results showed that the methylthioethyl derivative 61 was one of the most potent benzothiazolines with an ED50 of 1 mg/kg i.p. (Table 4). Surprisingly, the corresponding sulfoxide 64 and sulfone 65 were as active as their parent thioether. This might suggest that the active molecule in vivo is in fact a common metabolite.36 Lengthening or shortening the alkyl chain by one carbon atom (compounds 59, 60, and 69-71), as well as the replacement of the methylthio group by a thiol or larger and/or aromatic substituents (compounds 62, 63, 67, and 68), resulted in a loss of anticonvulsant effect; however, all compounds diplayed a reasonable level of activity (ED50 e 5 mg/kg i.p.). Looking at the aminocontaining series, in contrast to the monomethylated compound 72, the dimethylaminoethyl-substituted benzothiazoline 73 and the cyclic analogue 74 demonstrated good anticonvulsant potency with an ED50 value of about 2 mg/kg i.p. (Table 5). Homologation of 73 to the aminopropyl derivative 75 resulted in a reduced protective effect, thus indicating the β-position of the amino group to be preferable. Replacement in 73 of the

Riluzole Series


Table 8. Neuroprotective Activities of Selected Benzothiazolines ED50 (mg/kg i.p.) no.

Glua

H.H.b

61 64 65 73 74 78 79 80 81 riluzole

1.0 1.1 1.8 2.3 2.0 3.0 2.2 3.5 10.0 3.2

14.0 5.5 2.5-10 4.0 10 4.0

a Protection against glutamic acid-evoked convulsions in rats. The variability in this test is between 15 and 25%. b Protective effect against mortality induced by hypobaric hypoxia in mice. The variability in this test is 20%.

dimethylamino group by a group containing an aromatic moiety such as N-methyl-N-benzylamino group (76) or N-methyl-N-phenethylamino group (77) gave compounds with reduced potency. Unexpectedly however, the 4-phenyl-piperidinyl derivative 78 as well as the 4-phenyl-1,2,3,6-tetrahydropyridyl and 4-phenyl-piperazinyl analogues (compounds 79 and 80, respectively) displayed a high level of activity in the same range (ED50 ) 2-3 mg/kg i.p.). In this series, as for the aminated aliphatic one, lengthening of the alkyl chain (compound 81) decreased “antiglutamate” activity. To study simultaneous modifications at the 3- and 6-positions, the 6-trifluoromethoxy groups of three of the most active benzothiazolines were replaced by other substituents which had been shown previously to be the most efficient in the benzothiazole series, i.e., polyfluoroalkoxy, polyfluoroalkyl, and alkyl groups (Table 6). Surprisingly, from these three series of derivatives, only the 6-polyfluoroalkyl- (compounds 87 and 88) and 6-polyfluoroalkoxy- (compounds 73, 86, and 89) substituted compounds displayed high and comparable potencies, suggesting that the presence of an electronwithdrawing group containing fluorine atoms is of crucial importance. Furthermore, the importance of the 2-imino group in the thioalkyl series was illustrated by the slight (compound 90) or more dramatic (compound 91) decrease of activity observed with the 2-N-alkylated-iminobenzothiazolines. A decrease was also seen with the 2-Nhydroxylated and 2-N-acylated derivatives (compounds 92-94), as well as with the keto analogue 95 (Table 7). Neuroprotective Activities of Selected Compounds. Some of the most active and representative benzothiazolines have been evaluated for their protective effects against mortality induced by hypobaric hypoxia.37 As shown in Table 8, all compounds studied display high protective activities following i.p. administration. Activities in the hypobaric hypoxia model are very similar to that of riluzole, except for the thioether 61 which, surprisingly, is about 3 times less effective. ED50 values for the other compounds range between 2.5 and 10 mg/kg, thus showing the potential neuroprotective activity of riluzole derivatives. Conclusions A series of 6-substituted-2-benzothiazolamines was first evaluated against seizures induced by intracere-

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broventricular administration of glutamic acid in rats. Two sets of products were shown to be active in this model: compounds bearing a large but not too large alkyl substituent, and compounds bearing a polyfluoroalkyl or a polyfluoroalkoxy substituent. These biological data suggest that the 6-substituted-2-benzothiazolamine series possesses excitatory amino acid antagonist activity. This may endow members of this series with interesting anticonvulsive and neuroprotective properties. Indeed, riluzole, a lead in this series, has been shown to be neuroprotective in curative treatment in animal models of focal and global ischaemia17 and had been selected for clinical trials in amyotrophic lateral sclerosis where it showed efficacy in slowing disease progression. As a second step, 3-substituted-2-imino-benzothiazolines were evaluated in the same test. It was shown that a wide variety of modifications in the 3-position of riluzole were possible. Of all the analogues, compounds as active as riluzole or up to 3 times more potent were found among benzothiazolines bearing heteroatoms in the β-position of the alkyl substituent; the dialkylaminoethyl- and unchanged or oxidized alkylthioethyl-benzothiazolines are strong “antiglutamate” compounds in vivo, twice as active as the noncompetitive NMDA antagonist dizocilpine. The most potent glutamic acid antagonists in vivo protected mice against mortality induced by hypobaric hypoxia, a simple pharmacological test capable of predicting neuroprotective potential for these compounds. Anti-ischemic activities of RP 66055 (3-{2-[1-(4-fluorophenyl-piperazinyl)]ethyl}-2-imino-6trifluoromethoxybenzothiazoline), a fluorinated derivative of the benzothiazoline 80, were recently reported.38 Experimental Section Melting points were determined on a Ko¨fler apparatus and are uncorrected. 1H NMR spectra were recorded on a Bruker WP 200 (200 MHz), a Bruker WM 250 (250 MHz), or a Bruker AM 400 (400 MHz). IR spectra were taken on a FT-IR Nicolet 60 SX-R, a Perkin-Elmer 580 B, or a Perkin-Elmer 983 G. Mass spectra were recorded on a Finnigan 3300 spectrometer (EI at 70 eV) or on a Nermag R10-10B (DCl, NH3). NMR data are reported in ppm downfield relative to external TMS (0 ppm) as standard. Elemental analyses are indicated by the symbol of the elements, and the results were within ( 0.4% (for C, H, Br, Cl, F, N, S) of the theoretical values unless otherwise noted. Medium-pressure chromatographic separations were performed on silica gel (0.04-0.063 mm supplied by Merck). All organic solutions were dried over magnesium sulfate. Yields are not optimized. Compounds 1, 3, 5-9, 11, 12, 15-21, 30, and 37 were prepared according to literature procedures.19,39-52 Method A. 6-Pentyl-2-benzothiazolamine (23). 4-Pentylaniline (4.9 g; 0.03 mol), AcOH (45 mL), and potassium thiocyanate (11.6 g; 0.12 mol) were stirred at 19 °C for 10 min, and then a solution of bromine (1.5 mL; 0.03 mol) in AcOH (20 mL) was added over 20 min; during the addition, the temperature rose to 35 °C. The reaction mixture was stirred for 21 h at room temperature, then poured into cold water (600 mL), made alkaline with 28% aqueous NH4OH (∼90 mL), and extracted with EtOAc (250 + 150 mL). The organic phase was washed with water (150 mL), dried, filtered, and evaporated. A crude yellow product was obtained which was chromatographed on silica gel (500 g) eluted with 5:5 cyclohexaneEtOAc and crystallized from cyclohexane (55 mL) to yield 23 as white pearly crystals (4.3 g; 71%): mp 122 °C; NMR (DMSO, 200 MHz) δ 0.82 (t, 3H, CH3), 1.36 (m, 4H, 2 CH2), 1.55 (quint, 2H, CH2), 2.55 (t, 2H, CH2Ar), 6.97 (dd, 1H, H5), 7.22 (d, 1H, H4), 7.32 (bs, 2H, NH2), 7.92 (d, 1H, H7); IR (KBr) 820, 865,

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Jimonet et al.

1055, 1105, 1285, 1300, 1465, 1530, 1560, 1625, 2850, 2865, 2920, 2950, 3100, 3275, 3430 cm-1; MS m/z 220 (M+), 163 (M+ - (CH2)3CH3). Anal. (C12Hl6N2S) C, H, N, S. Fourteen other new compounds were synthesized according to method A: 13 (28%), Anal. (C11H14N2OS) C, H, N, S; 22 (68%), Anal. (C11H14N2S) C, H, N, S; 24 (65%), Anal. (C12H16N2S) C, H, N, S; 25 (54%), Anal. (C22H16N2S) C, H, N, S; 26 (41%), Anal. (C13H18N2S) C, H, N, S; 27 (65%), Anal. (C14H20N2S) C, H, N, S; 28 (29%), Anal. (C9H7F3N2S) C, H, F, N, S; 29 (11%), Anal. (C9H5F3N2OS) C, H, F, N, S; 31 (52%), Anal. (C8H6F2N2OS) C, H, F, N, S; 32 (43%), Anal. (C9H7F3N2OS) C, H; 33 (39%), Anal. (C10H7F5N2OS) C, H, F, N, S; 34 (50%), Anal. (C9H6F4N2OS) C, H, F, N, S; 35 (55%), Anal. (C9H5F5N2OS) C, H, F, N, S. Base 36 was converted to the hydrochloride and crystallized as noted in Table 1: 36 (18%), Anal. (C9H6F3NS‚ HCl) C, H, Cl, F, N. 4-(2,2,2-Trifluoroethyl)aniline. The starting material for 24 was prepared as follows: To a stirred solution of 4-(2,2,2trifluoroethyl)nitrobenzene53 (3.8 g; 0.0185 mol) in EtOH (20 mL) was added 5% Pd/C (0.17 g), and then a solution of hydrazine hydrate (1.8 mL; 0.036 mol) in EtOH (10 mL) was added dropwise over 20 min; during the addition the reaction temperature rose to 44 °C. After addition, the mixture was refluxed for 15 min and cooled to room temperature. The catalyst was filtered off, and the filtrate was concentrated, then diluted with water, and extracted with EtOAc (200 mL). The organic phase was dried and the solvent evaporated under reduced pressure to yield a yellow oil (2.7 g; 83%) which was purified by chromatography on silica gel. Elution with 7:3 cyclohexane-EtOAc gave 4-(2,2,2-trifluoroethyl)aniline as an oil (2.3 g; 71%): NMR (CDCl3, 200 MHz) δ 3.25 (q, J ) 10 Hz, 2 H, CH2CF3), 3.60 (mf, 2H, NH2), 6.66 (dd, 2H, H3, H5), 7.10 (bd, 2H, H2, H6); MS m/z 175 (M+), 106 (M+ - CF3). Method B. 4-(Trifluoromethoxy)-2-benzothiazolamine (38). Step 1. N-[2-(Trifluoromethoxy)phenyl]thiourea. A stirred solution of 2-(trifluoromethoxy)aniline54 (17.7 g; 0.1 mol), ammonium thiocyanate (8 g; 0.105 mol), sodium hydrogen sulfite (0.7 g), and 20% hydrochloric acid (18.2 mL) was heated at 90 °C for 14 h. The cooled mixture was filtered, washed with water to neutrality, triturated with isopropyl ether, filtered, and dried to give the desired product as a white solid (16 g; 68%): mp 157 °C; NMR (CDCl3, 200 MHz) δ 6.25 (mf, 2H, NH2), 7.30-7.60 (rnt, 5H, Ar), 7.87 (mf, 1H, NH); IR (KBr) 725, 775, 1065, 1155, 1175, 1220, 1265, 1310, 1450, 1490, 1520, 1590, 1615, 1625, 3030, 3075, 3150, 3250, 3425 cm-1; MS m/z 236 (M+), 219 (M+ - NH3), 151 (M+ - OCF3). Anal. (C8H7F3N2OS) C, H, F, N, S. In a similar way, starting from 3-(trifluoromethoxy)aniline (4 g; 0.024 mol), N-[3-(trifluoromethoxy)phenyl]thiourea was obtained as a white solid (1.7 g; 30%): mp 86 °C; MS m/z 236 (M+), 203 (M+ - SH). Step 2. 4-(Trifluoromethoxy)-2-benzothiazolamine (38). To a stirred suspension of N-[2-(trifluoromethoxy)phenyl]thiourea (16 g; 0.068 mol) in CHCl3 (130 mL) was added dropwise a solution of bromine (7 mL; 0. 136 mol) in CHCl3 (15 mL). The reaction mixture was refluxed for 2.5 h and allowed to stand at room temperature overnight. The mixture was evaporated to dryness in vacuo, and the orange residue was treated with diluted NH4OH and extracted with CH2Cl2 (2 × l50 mL), dried, filtered, and evaporated. A yellowish solid (14 g) was obtained which was crystallized twice from CCl4 to yield 38 as white crystals (6.5 g; 41%): mp 132 °C; NMR (CDCl3, 200 MHz) δ 7.08 (t, J ) 9 Hz, 1H, H6), 7.17 (mf, 2H, NH2), 7.21 (mt, 1H, H5), 7.5 (dd, 1H, H7); IR (KBr) 710, 785, 1055, 1175, 1250, 1285, 1430, 1470, 1540, 1575, 1605, 1640, 1645, 3100, 3250, 3295, 3495 cm-1; MS m/z 234 (M+), 214 (M+ - HF), 165 (M+ - CF3). Anal. (C8H5F3N2OS) C, H, F, N, S. By the same method, starting from N-[3-(trifluoromethoxy)phenyl]thiourea (12.8 g; 0.054 mol), 5-(trifluoromethoxy)-2benzothiazolamine (3 g) was obtained after chromatography on silica gel, eluting with 8:1:1 toluene-MeOH-diethylamine. The base was converted to the hydrochloride and washed with acetone to give 39 (3.2 g; 22%): mp 158 °C; NMR (base) (DMSO, 200 MHz) δ 7.00 (bd, J ) 8.0 Hz, 1H, H6), 7.27 (mf,

1H, H4), 7.75 (mf + d, 3H, NH2, H7); IR (KBr) 800, 865, 1175, 1215, 1250, 1485, 1550, 1600, 1610, 1650, 3050, 3150, 3280, 3400 cm-1; MS m/z 234 (M+), 207 (M+ - HCN), 165 (M+ CF3). Anal. (C8H5F3N2OS‚HCl) C, H, Cl, N, S. Method C. 7-(Trifluoromethoxy)-2-benzothiazolamine (40). Step 1. 2-Nitro-6-(trifluoromethoxy)acetanilide. Nitronium tetrafluoroborate (20 g; 0.15 mol) was added in small portions over 40 min to a stirred solution of 2-(trifluoromethoxy) acetanilide53 (21.9 g; 0.1 mol) in CH3CN (200 mL) cooled at -30 °C. The reaction mixture was allowed to stand at -5 °C for 30 min and was poured into cold water. The solid thus obtained was filtered off, washed with water, and then crystallized in toluene (200 mL) to give 2-nitro-6-(trifluoromethoxy)acetanilide (3.6 g). The filtrate was concentrated under reduced pressure and chromatographed on alumina (700 g) containing water (3% w/w), eluting with toluene then CH2Cl2 to afford another crop (1.5 g). Total yield was 19%: mp 160 °C; NMR (CDCl3, 200 MHz) δ 2.25 (s, 3H, COCH3), 7.41 (t, J ) 9 Hz, 1H, H4), 7.6 (d, J ) 9 Hz, 1H, H5), 7.88 (mf, 1H, NH), 7.95 (dd, 1H, H3); IR (KBr) 675, 695, 735, 815, 805, 1080, 1175, 1210, 1260-1275, 1365, 1450, 1475, 1510, 1450, 1595, 1610, 1675, 3270 cm-1; MS m/z 264 (M+), 221 (M+ - COCH3). Step 2. 2-Nitro-6-(trifluoromethoxy)aniline. A mixture of 2-nitro-6-(trifluoromethoxy) acetanilide (12.5 g; 0.0473 mol), EtOH (125 mL), and concentrated HCl (125 mL) was refluxed for 3.5 h, then concentrated under reduced pressure, poured onto ice-water (800 mL), made alkaline with 28% aqueous NH4OH (95 mL), and extracted with EtOAc (4 × 250 mL). The organic layer was dried and evaporated to yield 2-nitro-6(trifluoromethoxy)aniline as a yellow oil (9.9 g; 94%): NMR (CDCl3, 200 MHz) δ 6.35 (mf, 2H, NH2), 6.72 (dd, 1H, H4), 7.42 (bdd, 1H, H3), 8.10 (dd, 1H, H5); IR (CC14) 730, 1080, 1185, 1220, 1250, 1365, 1460, 1530, 1580, 1630, 3400, 3525 cm-1; MS m/z 222 (M+), 192 (M+ - NO), 153 (M+ - CF3). Step 3. 2-Iodo-3-(trifluoromethoxy)nitrobenzene. Iodine (65.8 g; 0.26 mol) followed by isoamylnitrite (10 mL; 0.075 mol) was added to a stirred solution of 2-nitro-6-(trifluoromethoxy)aniline (11 g; 0.05 mol) in CHCl3 (200 mL). The reaction mixture was refluxed for 4 h and allowed to stand at room temperature overnight. The liquid phase was taken off and concentrated to give a purple oil (18 g) which was chromatographed on silica gel (700 g), eluting with 8:2 cyclohexane-EtOAc. 2-Iodo-3-(trifluoromethoxy)nitrobenzene was thus obtained as a red oil (6.7 g; 40%) suitable for use in the following step. Step 4. 2-lodo-3-(trifluoromethoxy)aniline. A mixture of 2-iodo-3-(trifluoromethoxy)-nitrobenzene (7 g; 0.021 mol), EtOH (65 mL), H2O (65 mL), Fe (powder) (9.5 g), and concentrated HCl (2.2 mL) was refluxed for 4.5 h. The cooled mixture was poured into ice-water (500 mL), made alkaline with 28% aqueous NH4OH (10 mL), and extracted with EtOAc (5 × 200 mL). The organic phase was dried, evaporated, and chromatographed on silica gel (400 g), eluting with 8:2 cyclohexane-AcOEt to give 2-iodo-3-(trifluoromethoxy)aniline as a light brown oil (4.1 g; 64%): NMR (DMSO, 300 MHz) δ 6.55 (d, J ) 9 Hz, 1H, H4), 6.74 (dd, 1H, H6), 7.15 (t, J ) 9 Hz, 1H, H5); IR (CCl4) 715, 1025, 1080, 1170, 1215, 1265, 1460, 1470, 1570, 1615, 3070, 3375, 3475 cm-1; MS m/z 303 (M+), 175 (M+ - HI). Step 5. 7-(Trifluoromethoxy)-2-benzothiazolamine (40). A mixture of 2-iodo-3-(trifluoromethoxy)aniline (3.7 g; 0.012 mol), DMF (120 mL), thiourea (3.7 g), bis(triethylphosphine)NiII (1.8 g), and sodium cyanoborohydride (1.5 g) was heated at 85 °C with stirring for 16 h. Additional bis(triethylphosphine)NiII (1 g) and NaBH3CN (0.7 g) were added, and heating was kept at 85 °C for 6 h. The reaction mixture was poured into water (600 mL) and extracted with EtOAc (5 × l00 mL). The organic layer was dried, evaporated, and chromatographed on silica gel (600 g), eluting with 2:1 cyclohexane-EtOAc to yield 40 (0.4 g; 14%). After a second chromatography (the same eluting mixture), an analytical sample melted at 108 °C: NMR (CDCl3, 200 MHz) δ 5.35 (mf, 2H, NH2), 7.05 (bd, 1H, H6), 7.33 (t, 1H, H5), 7.60 (dd, 1H, H4). IR (KBr) 710, 775, 1060, 1110, 1120, 1160, 1220, 1260, 1290, 1435, 1480, 1530, 1550,

Riluzole Series


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1570, 1610, 1630, 3120, 3280, 3360 cm-1; MS m/z (234 M+), 207 (M+ - HCN), 165 (M+ - CF3). Anal. (C8H5F3N2OS) C, H, N, S. Method D. 6-(Trimethylsilyl)-2-benzothiazolamine (14). A 1.6 M solution of n-BuLi in hexane (46 mL) was added with stirring under Ar to a -70 °C cooled solution of 5 (6.8 g; 0.03 mol) in dry THF (100 mL), followed by a solution of chlorotrimethylsilane (9.3 mL; 0.04 mol) in dry THF (10 mL) at 0 °C. After the temperature was allowed to rise to 20 °C, the reaction mixture was refluxed for 1.5 h and then cooled to -10 °C before additional n-BuLi solution (19 mL) was added. The temperature was allowed to rise to 0 °C, and to the light red solution thus obtained was added a solution of chlorotrimethylsilane (4.7 mL; 0.037 mol) in dry THF (10 mL). During the addition, the temperature rose to 17 °C, and then the reaction mixture was refluxed for 4.5 h. The cooled mixture was poured into water (100 mL), alkalized with 28% aqueous NH4OH, and extracted with CH2Cl2 (4 × 200 mL). The lower layer was dried, filtered, and evaporated in vacuo. The orange oil (10.1 g) thus obtained was chromatographed twice on silica gel using a 6:4 mixture of EtOAc-cyclohexane to yield a white solid (0.55 g). This material was triturated with 40/65 petroleum ether, filtered, and dried to yield 14 (0.45 g; 7%): mp 140 °C; NMR (DMSO, 200 MHz) δ 0.25 (mf, 9H, (CH3) 3Si), 7.34 (s, 2H, H4, H5), 7.53 (mf, 2H, NH2), 7.78 (s, 1H, H7); IR (KBr) 840, 900, 1050, 1105, 1150, 1245, 1260, 1300, 1380, 1445, 1455, 1520, 1545, 1585, 1632, 2895, 2950, 3090, 3280, 3425 cm-1; MS m/z 222 (M+), 207 (M+ - CH3). Anal. (C10H14N2SSi) C, H, N, S. General Procedures for 3-N-Alkylation of 6-Substituted-2-benzothiazolamine (Methods F-I). Method F. 3-(2-Methylthio-ethyl)-2-imino-6-trifluoromethoxy-benzothiazoline Hydrochloride (61). A stirred suspension of 6-trifluoromethoxy-2-benzothiazolamine 1 (10 g, 0.0427 mol) and 2-methylthioethyl chloride (5 mL, 0.050 mol) in 20 mL of methyl ethyl ketone (MEK) was heated under reflux for 24 h. After cooling to room temperature, the resulting precipitate was filtered and washed twice with 20 mL of MEK to give 61 (11.5 g, 78%) as a colorless solid: mp 208 °C; 1H NMR δ (200 MHz, DMSO-d6) 2.17 (s, 3H, SCH3), 2.9 (t, 2H, J ) 7 Hz, CH2S), 4.6 (t, 2H, J ) 7 Hz, NCH2), 7.58 (bd, 1H, 5-H), 7.8 (d, 1H, J ) 9 Hz, 4-H), 8.19 (bs, 1H, 7-H), 10.0-1 1.7 (m, 2H, dNH‚HCl); MS m/e 308 (M+), 234 (100). Anal. (C11H11F3N2OS2‚HCl) C, H, Cl, F, N, S. Compounds 41-50, 52, 53, 59, 62, 63, 67, 73-75 were prepared from 1 in the same way as 61 using the appropriate alkylating reagents. Compounds 82 and 83 were prepared from 22 and 2, respectively. 2-Imino-3-methyl-6-trifluoromethoxy-benzothiazoline (41): mp 60-62 °C; 1H NMR δ (200 MHz, DMSO-d6) 3.41 (s, 3H, NCH3), 7.2 (d, 1H, J ) 9 Hz, 4-H), 7.31 (bd, 1H, 5-H), 7.7 (bs, 1H, 7-H); MS m/e 248 (M+), 220 (100). Anal. (C9H7F3N2OS) C, H, F: calcd, 22.96; found, 22.08; N, S. 3-Ethyl-2-imino-6-trifluoromethoxy-benzothiazoline Hydrochloride (42): mp 234 °C; 1H NMR δ (200 MHz, DMSO-d6) 0.8 (t, 3H, J ) 7 Hz, NCH2CH3), 4.42 (q, 2H, J ) 7 Hz, NCH2CH3), 7.6(bd, 1H, 5-H), 7.85 (d, 1H, J ) 9 Hz, 4-H), 8.2 (bs, 1H, 7-H), 11.3-12.7 (m, 2H, NH‚HCl); MS m/e 262 (M+), 234 (80),165 (100). Anal. (C10H9F3N2OS‚HCl) C, H, Cl, F, N, S. 2-Imino-3-propyl-6-trifluoromethoxy-benzothiazoline Hydrochloride (43): mp 231 °C dec; 1H NMR (base) δ (200 MHz, DMSO-d6) 0.91 (t, 3H, J ) 7.5 Hz, NCH2CH2CH3), 1.62 (m, 2H, NCH2CH2CH3), 3.86 (t, 2H, J ) 7.5 Hz, NCH2CH2CH3), 7.1 (d, 1H, J ) 9 Hz, 4-H), 7.2 (bd, 1H, 5-H), 7.58 (bs, 1H, 7-H), 8.4 (bs, 1H, NH); MS m/e 276 (M+), 234 (100), 165 (80). Anal. (C11H11F3N2OS‚HCl) C, H, Cl, N, S. 3-Butyl-2-imino-6-trifluoromethoxy-benzothiazoline Hydrobromide (44): mp 243 °C; 1H NMR δ (200 MHz, DMSO-d6) 0.9 (t, 3H, J ) 7.5 Hz, NCH2CH2CH2CH3), 1.38 (m, 2H, NCH2CH2CH2CH3), 1.63 (m, 2H, NCH2CH2CH2CH3), 4.29 (t, 2H, J ) 7.5 Hz, NCH2CH2CH2CH3), 7.6 (bd, 1H, 5-H), 7.86 (d, 1H, J ) 9 Hz, 4-H), 8.21 (bs, 1H, 7-H), 10.0-10.8 (m, 2H, dNH‚HBr); MS m/e 290 (M+), 234 (100), 165 (85). Anal. (C12H13F3N2OS‚HBr) C, H, Br, F, N, S.

3-Allyl-2-imino-6-trifluoromethoxy-benzothiazoline Hydrobromide (45): mp 225 °C; 1H NMR δ (200 MHz, DMSOd6) 5.0 (d, 2H, J ) 4.5 Hz, NCH2), 5.22 and 5.29 (d, J ) 16 Hz, and d, J ) 10 Hz, NCH2CHdCH2), 5.95 (m, 1H, NCH2CHd CH2), 7.59 (bd, 1H, 5-H), 7.76 (d, 1H, J ) 9 Hz, 4-H), 8.22 (bs, 1H, 7-H), 10.0-11.0 (m, 2H, dNH‚HBr); MS m/e 274 (M+), 259 (80). Anal. (C11H9F3N2OS‚HBr) C, H, Br, F, N, S. 2-Imino-3-(2-propynyl)-6-trifluoromethoxy-benzothiazoline Hydrobromide (46): mp 210 °C (sublimes); 1H NMR δ (200 MHz, DMSO-d6) 3.69 (bs, 1H, NCH2CtCH), 5.32 (bs, 2H, NCH2CtCH), 7.63 (bs, 1H, 5-H), 7.87 (d, 1H, J ) 9 Hz, 4-H), 8.27 (bs, 1H, 7-H), 10.4-11.1 (m, 2H, dNH‚HBr); MS m/e 272 (M+), 271 (85). Anal. (C11H7F3N2OS‚HBr) C, H, Br, F, N, S. 3-(2-Cyanoethyl)-2-imino-6-trifluoromethoxy-benzothiazoline Oxalate (47): mp 180 °C; 1H NMR δ (200 MHz, DMSO-d6) 3.00 (t, 2H, J ) 7 Hz, CH2CN), 4.42 (t, 2H, J ) 7 Hz, NCH2), 5.00-5.80 (bb, 3H, dNH‚(COOH)2), 7.42 (bd, 1H, J ) 8 Hz, 5-H), 7.63 (d, J ) 8 Hz, 1H, 4-H), 7.87 (bs, 1H, 7-H); MS m/e 286 (M - 1+), 233 (100); (CI+) 288 (M + 1+). Anal. (C11H8F3N3OSC2H2O4) C, H, F, N, S. 3-Benzyl-2-imino-6-trifluoromethoxy-benzothiazoline Hydrobromide (48): mp 200 °C (sublimes); 1H NMR δ (200 MHz, DMSO-d6) 5.65 (m, 2H, NCH2), 7.25-7.50 (m, 5H, ArH), 7.55 (bd, 1H, 5-H), 7.68 (d, 1H, J ) 9 Hz, 4-H), 8.25 (bs, 1H, 7-H), 10.3-11.0 (m, 2H, dNH‚HBr); MS m/e 324 (M+), 91 (100). Anal. (C15H11F3N2OS‚HBr‚H2O) C, H, Br, F, N, S. 2-Imino-3-phenethyl-6-trifluoromethoxy-benzothiazoline Hydrobromide (49): mp 210 °C (sublimes); 1H NMR δ (250 MHz, DMSO-d6) 3.03 (t, 2H, J ) 7.5 Hz, NCH2CH2Ar), 4.57 (t, 2H, J ) 7.5 Hz, NCH2CH2Ar), 7.15-7.4 (m, 5H, ArH), 7.5 (bd, 1H, 5-H), 7.71 (d, 1H, J ) 9 Hz, 4-H), 8.2 (bs, IH, 7-H), 10.2-10.7 (m, 2H, dNH‚HBr); MS m/e 338 (M+), 234 (100). Anal. (C16H13F3N2OS‚HBr) C, H, Br, F, N, S. 2-Imino-3-methoxycarbonylmethyl-6-trifluoromethoxybenzothiazoline Hydrobromide (50): mp 246 °C dec; 1H NMR δ (200 MHz, DMSO-d6) 3.77 (s, 3H, CO2CH3), 5.37 (s, 2H, NCH2CO2), 7.6 (bd, 1H, 5-H), 7.84 (d, 1H, J ) 9 Hz, 4-H), 8.24 (bs, 1H, 7-H), 10.2-11.2 (m, 2H, dNH‚HBr); MS m/e 306 (M+), 247 (100), 220 (95). Anal. (C11H9F3N2O3S‚HBr) C, H, Br, F, N, S. 3-Aminocarbonylmethyl-2-imino-6-trifluoromethoxybenzothiazoline (52): mp 228 °C; 1H NMR δ (200 MHz, DMSO-d6) 4.53 (bb, 2H, NCH2CO), 6.96 (d, 1H, J ) 8.5 Hz, 4-H), 7.20 (bd, 1H, J ) 8.5 Hz, 5-H), 7.25 and 7.65 (two bb, 1H each, CONH2), 7.60 (bs, 1H, 7-H), 8.45 (bb, 1H, dNH); MS m/e 291 (M+), 220 (100). Anal. (C10H8F3N3O2S) C, H, F, N, S. 3-Diethylaminocarbonylmethyl-2-imino-6-trifluoromethoxy-benzothiazoline Hydrochloride (53): mp 223 °C; 1H NMR δ (250 MHz, DMSO-d6) 1.05 and 1.32 (t, 1H each, J ) 7 Hz, CON(CH2CH3)2, 3.31 and 3.49 (q, 2H each, J ) 7 Hz, CON(CH2CH3)2), 5.55 (s, 2H, NCH2CO), 7.57 (bd, 1H, 5-H), 7.62 (d, 1H, J ) 9 Hz, 4-H), 8.19 (bs, 1H, 7-H), 10.6-11.6 (m, 2H, dNH‚HCl); MS m/e 347 (M+), 113 (100). Anal. (C14H16F3N3O2S‚lHCl) C, H, Cl, F: calcd, 14.85; found, 14.30; N, S. 3-Methylthiomethyl-2-imino-6-trifluoromethoxy-benzothiazoline Hydrochloride (59): mp 170 °C (sublimes); 1H NMR δ (200 MHz, DMSO-d6) 2.2 (s, 3H, SCH3), 5.76 (s, 2H, NCH2S), 7.6 (bd, 1H, 5-H), 7.91 (d, 1H, J ) 9 Hz, 4-H), 8.2 (bs, 1H, 7-H), 10.85-11.4 (m, 2H, dNH‚HCl); MS m/e 294 (M+), 247 (100). Anal. (C10H9F3N2OS2‚HCl) C, H, Cl, F, N, S. 3-(2-Ethylthio-ethyl)-2-imino-6-trifluoromethoxy-benzothiazoline Hydrochloride (62): mp 160 °C (sublimes); 1H NMR δ (200 MHz, DMSO-d6) 1.12 (t, 3H, J ) 7.5 Hz, SCH2CH3), 2.65 (q, 2H, J ) 7.5 Hz, SCH2CH3), 2.93 (t, 2H, J ) 7 Hz, CH2S), 4.61 (t, 2H, J ) 7 Hz, NCH2), 7.58 (bd, 1H, 5-H), 7.8 (d, 1H, J ) 9 Hz, 4-H), 8.2 (bs, 1H, 7-H), 10.2-11.4 (m, 2H, dNH‚HCl); MS m/e 322 (M+), 234 (100). Anal. (C12H13F3N2OS2‚HCl) C, H, Cl, F, N, S. 2-Imino-3-(2-propylthio-ethyl)-6-trifluoromethoxy-benzothiazoline Hydrochloride (63): mp 187 °C; 1H NMR δ (200 MHz, DMSO-d6) 0.87 (t, 3H, J ) 7.5 Hz, SCH2CH2CH3), 1.47 (m, 2H, SCH2CH2CH3), 2.56 (t, 2H, J ) 7 Hz, SCH2CH2CH3), 2.91 (bt, 2H, J ) 7 Hz, NCH2CH2S), 4.56 (t, 2H, J ) 7

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Hz, NCH2CH2S), 7.6 (bd, 1H, 5-H), 7.8 (d, IH, J ) 9 Hz, 4-H), 8.16 (bs, 1H, 7-H), 10.5-11.5 (m, 2H, dNH‚HCl); MS m/e 336 (M+), 234 (100). Anal. (C13H15F3N2OS2-HCl) C, H, Cl, F, N, S. 2-Imino-3-(2-phenylthio-ethyl)-6-trifluoromethoxy-benzothiazoline Hydrochloride (67): mp 174 °C; 1H NMR δ (200 MHz, DMSO-d6) 3.5 (t, 2H, J ) 6.5 Hz, NCH2CH2S), 4.65 (t, 2H, J ) 6.5 Hz, NCH2CH2S), 7.15 (m, 5H, ArH), 7.49 (bd, 1H, 5-H), 7.6 (d, 1H, J ) 9 Hz, 4-H), 8.02 (bs, 1H, 7-H), 10.511.5 (m, 2H, dNH‚HCl); MS m/e 371 (M+), 234 (90), 136 (100). Anal. (C16H13F3N2OS2‚HCl) C, H, Cl, F, N, S. 3-(2-Dimethylamino-ethyl)-2-imino-6-trifluoromethoxybenzothiazoline Dihydrochloride (73): mp 200 °C (sublimes); 1H NMR δ (200 MHz, DMSO-d6) 2.92 (s, 6H, N(CH3)2), 3.5 (t, 2H, J ) 6 Hz, NCH2CH2NMe2), 4.85 (t, 2H, J ) 6 Hz, NCH2CH2NMe2), 7.51 (bd, 1H, 5-H), 8.18 (d, 1H, J ) 9 Hz, 4-H), 8.2 (bs, 1H, 7-H), 10.7-11.7 (m, 3H, dNH‚HCl and NR3‚ HCl); MS m/e (CI+) 306 (M + 1+). Anal. (C12H14F3N3OS‚2HCl) C: calcd, 38.11; found, 38.70; H, Cl, F, N, S. 2-Imino-3-(2-piperidino-ethyl)-6-trifluoromethoxy-benzothiazoline Dihydrochloride (74): mp 200 °C (sublimes); 1H NMR δ (200 MHz, DMSO-d ) 1.3-2.0 (m, 6H, H-piperidine), 6 3.15 and 3.47 (m, 2H and 4H, N(piperidine)-CH2), 4.88 (t, 2H, J ) 6.5 Hz, NCH2CH2N(piperidine, 7.6 (bd, 1H, 5-H), 8.07 (bs, 1H, 7-H), 8.24 (d, 1H, J ) 9 Hz, 4-H), 10.5-11.5 (m, 3H, d NH‚HCl and NR3‚HCl); MS m/e 346 (M+), 111 (70), 98 (100); Anal. (C15H18F3N3OS‚2HCl) C, H, Cl, F, N, S. 3-(3-Dimethylamino-propyl)-2-imino-6-trifluoromethoxy-benzothiazoline Oxalate (75): mp 218 °C; 1H NMR δ (200 MHz, DMSO-d6) 2.05 (m, 2H, NCH2CH2CH2NMe2), 2.76 (s, 6H, N(CH3)2), 3.14 (t, 2H, J ) 6 Hz, CH2NMe2), 4.12 (t, 2H, J ) 6 Hz, NCH2CH2CH2NMe2), 7.38 (bd, 1H, 5-H), 7.48 (d, 1H, J ) 9 Hz, 4-H), 7.81 (bs, 1H, 7-H); MS m/e 319 (M+), 248 (100); Anal. (C13H16F3N3OS‚1.6C2H2O4) C, H, F: calcd, 12.54; found, 11.90; N, S. 3-(2-Dimethylaminoethyl)-2-imino-benzothiazoline Dihydrochloride (82): mp 200 °C (sublimes); 1H NMR δ (200 MHz, DMSO-d6) 2.90 (s, 6H, N(CH3)2), 3.50 (CH2NMe2, this signal is overlapped by DOH signal of (CD3)2SO), 4.82 (bt, 2H, J ) 7.5 Hz, NCH2), 7.42 and 7.58 (2t, 1H each, J ) 8 Hz, 5-H and 6-H), 8.00 and 8.05 (2d, 1H each, J ) 8 Hz, 4-H and 7-H), 10.50-11.60 (very bb, 3H, dNH‚HCl and NR3‚HCl); MS m/e 221 (M+), 71 (100). Anal. (C11H15N3S‚2.0HCl) C, H, Cl, N, S. 6-tert-Butyl-3-(2-dimethylaminoethyl)-2-imino-benzothiazoline Dihydrochloride (83): mp 200 °C (sublimes); 1H NMR δ (200 MHz, DMSO-d6) 1.32 (s, 9H, C(CH3)3), 2.92 (s, 6H, N(CH3)2), 3.50 (bb, 2H, NCH2CH2NMe2), 4.87 (bb, 2H, NCH2CH2NMe2), 7.60 (bd, 1H, J ) 8.5 Hz, 5-H), 8.05 (bd, 1H, J ) 8 Hz, 4-H), 8.10 (bs, 1H, 7-H), 11.25 (bb, 2H, dNH‚HCl); MS m/e 277 (M+), 71 (100). Anal. (C15H23N3S‚2.0HCl) C: calcd, 51.42; found, 50.7; H, Cl, N, S. Method G. 2-Imino-3-[2-(4-phenyl-1-piperazinyl)-ethyl]6-trifluoromethoxy-benzothiazoline Hydrochloride (80). Ethyl trifluoroacetate (17 g, 0.12 mol) was added slowly to a stirred suspension of 3-(2-hydroxy-ethyl)-2-imino-6-trifluoromethoxy-benzothiazoline 5824 (27.8 g, 0.1 mol) and triethylamine (1 6 mL, 0.11 mol) in 200 mL of absolute ethanol at room temperature. The reaction mixture was stirred overnight at room temperature. The solvent was then removed, and the solid residue dissolved in boiling ethanol/water (1:1); the solution was cooled, and the white precipitate was collected and washed with the same solvent to provide the trifluoroacetylated compound 59 (32 g, 85%): mp 141 °C; 1H NMR δ (200 MHz, DMSO-d6) 3.85 (bq, 2H, J ) 5 Hz, NCH2CH2OH), 4.60 (bt, 2H, J ) 5 Hz, NCH2CH2OH), 5.00 (bt, 1H, NCH2CH2OH), 7.66 (bd, 1H, J ) 8.5 Hz, 4-H), 8.03 (d, 1H, J ) 8.5 Hz, 4-H), 8.25 (bs, 1H, 7-H); MS m/e 374 (M+), 45 (100). The imino-protected alcohol 98 (53 g, 0.14 mol) was added slowly to an ice-cooled solution of p-toluenesulfonyl chloride in 120 mL of dry pyridine. The reaction mixture was stirred overnight at room temperature. The solution was then poured onto ice and acidified to pH 4 with concentrated HCl. The resulting solid was collected and washed several times with water to give 100 (68 g, 90%), mp 145 °C, then solidified to

melt at 220 °C (mp of tosylate of 97). 100: 1H NMR δ (200 MHz, DMSO-d6) 2.37 (s, 3H, ArCH3), 4.57 (t, 1H, J ) 5 Hz, CH2OTos), 4.80 (t, 1H, J ) 5 Hz, NCH2, 7.16 and 7.32 (2d, 2H each, J ) 8 Hz, ArH), 7.68 (bd, 1H, J ) 8.5 Hz, 5-H), 7.98 (d, 1H, J ) 8.5 Hz, 4-H), 8.25 (bs, 1H, 7-H); MS m/e 528 (M+), 91 (100). To a stirred solution of 100 (6.9 g, 13 mmol) in 100 mL of dimethylfonnamide were added NaHCO3 (1.1 g, 13 mmol) and N-phenylpiperazine (2.4 g, 14 mmol). The mixture was heated to 80 °C overnight. After cooling, the reaction mixture was concentrated to dryness in vacuo, and water was added to the yellow residue. Extraction of the organic phase with ethyl acetate gave the pure trifluoroacetylated precursor of 80 after purification by flash chromatography using 80:20 EtOAc/ cyclohexane as eluent (2.4 g, 36%): mp 88 °C; 1H NMR δ (400 MHz, DMSO-d6) 3.00-4.00 (m, 10H, N(piperazine)-CH2), 5.00 (m, 2H, NCH2CH2N(piperazine)), 6.90 (t, 1H, J ) 7.5 Hz, 4′ArH), 7.00 (d, 2H, J ) 7.5 Hz, 2′-ArH), 7.33 (t, 2H, J ) 7.5 Hz, 3′-ArH), 7.74 (bd, 1H, J ) 8.5 Hz, 5-H), 8.22 (d, 1H, J ) 8.5 Hz, 4-H), 8.30 (bs, 1H, 7-H), 11.00 (bs, 1H, NR3‚HCl); MS m/e 518 (M+), 132 (100). A solution of the protected compound prepared above (1.06 g, 1.9 mmol) in a mixture of saturated aqueous K2CO3 (12 mL) and methanol (50 mL) was stirred at room temperature for 5 h. Methanol was then removed under reduced pressure and the organic phase extracted with EtOAc. EtOAc was evaporated and the crude product transformed into HCl salt to give 80 (0.78 g, 89%): mp 230 °C; 1H NMR δ (400 MHz, DMSO-d6) 3.0-3.5 (m, 10H, N(piperazine)-CH2), 4.67 (m, 2H, NCH2CH2N(piperazine)), 6.83 (t, 1H, J ) 7.5 Hz, ArH), 6.99 (d, 2H, J ) 7.5 Hz, ArH), 7.25 (t, 2H, J ) 7.5 Hz, ArH), 7.56 (bd, 1H, 5-H), 7.96 (d, 1H, J ) 9 Hz, 4-H), 8.1 (bs, 1H, 7-H), 10.0-11.5 (m, 2H, dNH‚HCl); MS m/e 422 (M+), 188 (95), 132 (100); (FAB+) 423 (M + 1+); Anal. (C20H21F3N4OS‚1HCl) C, H, Cl, F, N, S. Compounds 69 and 81 were prepared from 96 following an analogous synthetic pathway. 3-(3-Methylthio-propyl)-2-imino-6-trifluoromethoxybenzothiazoline Hydrochloride (69): mp 181 °C; 1H NMR δ (400 MHz, DMSO-d6) 1.98 (m, 2H, NCH2CH2CH2SMe), 2.06 (s, 3H, SCH3), 2-64 (t, 2H, J ) 7 Hz, NCH2CH2CH2SMe), 4.42 (t, 2H, J ) 7 Hz, NCH2CH2CH2SMe), 7.6 (bd, 1H, 5-H), 7.83 (d, 1H, J ) 9 Hz, 4-H), 8.17 (bs, 1H, 7-H), 10.5-11.2 (m, 2H, dNH‚HCl); MS m/e 321 (M+), 248 (100), 220 (90). Anal. (C12H13F3N2OS2‚HCl) C, H, Cl, F, N. 2-Imino-3-(3-(4-phenyl-1-piperazinyl)propyl)-6-trifluoromethoxy-benzothiazoline Dihydrochloride (81): mp 260 °C; 1H NMR δ (200 MHz, DMSO-d6) 2.25 (m, 2H, NCH2CH2CH2N(piperazine)), 3.1-3.95 (m, 10H, N(piperazine)CH2, 4.52 (t, 2H, J ) 7 Hz, NCH2CH2CH2N(piperazine)), 6.88 (t, 1H, J ) 7.5 Hz, ArH), 7.01 (d, 2H, J ) 7.5 Hz, ArH), 7.28 (t, 2H, J ) 7.5 Hz, ArH), 7.63 (bd, 1H, 5-H), 7.99 (d, 1H, J ) 9 Hz, 4-H), 8.19 (bs, 1H, 7-H), 10.8-11.3 (m, 3H, dNH‚HCl and NR3‚HCl); MS m/e 304 (70), 248 (80), 201 (65), 173 (100), 132 (95), 106 (90); (CI+) 437 (M + 1+); Anal. (C21H23F3N4OS‚ 2HCl) C: calcd, 49.51; found, 48.7; H, Cl, F, N, S. 3-(3-Hydroxypropyl)-2-imino-6-trifluoromethoxy-benzothiazoline Hydrobromide (96). Compound 96 was prepared from 6-trifluoromethoxy-2-benzothiazolamine, following method F: mp 181 °C; 1H NMR δ (200 MHz, DMSO-d6) 1.90 (m, 2H, NCH2CH2CH2OH), 3.50 (t, J ) 6 Hz, 2H, NCH2CH2CH2OH), 4.35 (t, 2H, J ) 6 Hz, N-CH2CH2CH2OH), 7.60 (bd, 1H, J ) 8 Hz, 5-H), 7.82 (bd, 1H, J ) 8 Hz, 4-H), 8.22 (bs, 1H, 7-H), 10.0-10.3 (bb, 2H, dNH‚HBr); Anal. (C11H11F3N2O2S‚ HBr) C, H, Br, F, N, S. Method H. 3-[2-(4-phenyl-1-piperidinyl)-ethyl]-6-trifluoromethoxy-2-imino-benzothiazoline (39). 4-Trifluoromethoxy-aniline (88.5 g, 0.5 mol) and 2-bromo-ethanol (31.2 g, 0.25 mol) were heated at 160 °C for 1.5 h. After cooling, the mixture was suspended in 200 mL of CH2Cl2, and the resulting solid was collected to provide the hydrobromide of the starting material (44.1 g). The filtrate was evaporated in vacuo to give 74 g of an oily residue which was purified by flash chroma-

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tography (EtOAc/cyclohexane 40:60) to give the alcohol 102 (26.8 g, 49%) as a yellow oil. To an ice-cooled and stirred solution of the alcohol 102 (20.9 g, 0.095 mol) and Et3N (26.7 mL, 0.19 mol) in 200 mL of CH2Cl2 was added dropwise p-toluenesulfonyl chloride (36.2 g, 0.19 mol). The mixture was stirred for 1.5 h at 0 °C and then allowed to reach ambient temperature. After dilution with 200 mL of CH2Cl2, the organic phase was washed with water, dried (MgSO4), and evaporated to give 48.4 g of an oily residue which was crystallized in absolute ethanol. This gave the ditosylate 103 (27.6 g, 55%) as a white solid, mp 88 °C. A stirred solution of the ditosylate 103 (7.2 g, 13.6 mmol), NaHCO3 (2.4 g, 28.6 inmol), and 4-phenylpiperidine (4.85 g, 28.6 mmol) in 50 mL of DMF was heated at 80 °C overnight (ca. 18 h). The solvent was evaporated in vacuo and the residue washed twice with water. The crude product was added to a solution of concentrated HCl (30 mL), acetic acid (30 mL), and water (20 mL), and the mixture was heated at 110 °C for 3 h. After cooling, the reaction mixture was poured into 100 mL of water and treated by aqueous K2CO3. The resulting solid was collected and recrystallized in 2-propanol to give 106 (6.2 g, 85%) as the p-toluenesulfonate salt, mp 176 °C. To a suspension of the substituted aniline 106 (2.96 g, 8.12 mmol), obtained by treatment of the p-toluenesulfonate salt with 1 N NaOH, and KSCN (3.17 g, 32.5 mmol) in acetic acid (15 mL), a solution of bromine (1.29 g, 8.12 mmol) in acetic acid (15 mL) was added dropwise. The reaction was allowed to continue overnight at room temperature. The mixture was poured into 100 mL of water, neutralized by 30% NaOH solution, and then extracted twice with EtOAc (200 mL). The extracts were dried and concentrated in vacuo to give 3.0 g of crude product. The dark oily residue was purified by flash chromatography using EtOAc as eluent to afford 78 (2.06 g, 60%) transformed into diHCl salt in Et2O: mp 220 °C (sublimes); 1H NMR δ (200 MHz, DMSO-d6) 1.95-2.25(m, 4H, piperidine-CH2), 2.9 (m, 1H, piperidine-CH), 3.27 (m, 2H, piperidine-axial NCH2), 3.55 (bt, 2H, J ) 7 Hz, NCH2CH2piperidine), 3.68 (bd, 2H, J ) 12.5 Hz, piperidine-equatorial NCH2), 4.91 (bt, 2H, J ) 7 Hz, NCH2CH2piperidine), 7.157.4 (m, 5H, ArH), 7.55 (bd, 1H, 5-H), 8.1 (bs, 1H, 7-H), 8.2(d, 1H, J ) 9 Hz, 4-H), 11.35 (m, 2H, dNH‚HCl); MS m/e 421 (M+), 187 (100), 174 (80). Anal.(C21H22F3N3OS‚2HCl) C, H, Cl, F, N, S. Compounds 76, 77, and 79 were prepared following an analogous synthetic pathway. 3-[2-(N-benzyl-N-methyl-amino)ethyl]-2-imino-6-trifluoromethoxy-benzothiazoline Hydrochloride (76): mp 180 °C; 1H NMR δ (200 MHz, DMSO-d6) 2.55 (s, 3H, NCH3), 3.05 (m, 2H, CH2N(Me)benzyl), 3.96 (bs, 2H, NCH2Ph), 4.63 (m, 2H, NCH2CH2N(Me)benzyl), 7.27 (m, 5H, ArH), 6.8-7.5 (m, 2H, dNH‚HCl), 7.44 (bd, 1H, 5-H), 7.74 (d, 1H, J ) 9 Hz, 4-H), 8.07 (bs, 1H, 7-H); MS m/e (CI+) 382 (M + 1+). Anal. (C18H18F3N3OS‚1HCl) C: calcd, 51.74; found, 51.0; H, Cl, F, N, S. 2-Imino-3-[2-(N-methyl-N-phenethyl-amino)ethyl]-6trifluoromethoxy-benzothiazoline Dihydrochloride (77): mp 216 °C; 1H NMR δ (200 MHz, DMSO-d6) 3.02 (s, 3H, N + CH3), 3.0-3.55 (m, 4H, N + (Me)CH2CH2Ph), 3.61 (t, 2H, J ) 6 Hz, NCH2CH2N + (Me) (CH2)2Ph), 4.94 (t, 2H, J ) 6 Hz, NCH2CH2N + (Me)CH2CH2Ph), 7.34 (m, 5H, ArH), 7.2-7.5 (m, 1H, NR3‚HCl), 7.64 (bd, 1H, 5-H), 8.2 (bs, 1H, 7-H), 8.23 (d, 1H, J ) 9 Hz, 4-H), 10.9-11.9 (m, 2H, dNH‚HCl); MS m/e (CI+) 396 (M + 1+). Anal. (C199H20F3N3OS‚2HCl) C, H, Cl, F, N, S. 2-Imino-3-[2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)ethyl]-6-trifluoromethoxy-benzothiazoline Dihydrochloride (79): mp 256 °C; 1H NMR δ (300 MHz, DMSO-d6) 2.9 (m, 2H, 3-pyridyl-CH2), 3.65 (m, 4H, NCH2CH2N + pyridyl and 2-pyridyl-CH2), 4.12 (m, 2H, 6-pyridyl-CH2), 4.95 (t, 2H, NCH2CH2N + pyridyl), 6.27 (bs, 1H, CH2CH‚C(Ph), 7.3-7.6 (m, 5H, ArH), 7.0-7.9 (m, 1H, NR3‚HCl), 7.6 (bd, 1H, 5-H), 8.19 (bs, 1H, 7-H), 8.25 (d, 1H, J ) 9 Hz, 4-H), 10.9-11.9 (m, 2H, d NH‚HCl); MS m/e 419 (M+), 185 (100). Anal. (C21H20F3N3OS‚ 2HCl) C, H, Cl, F, N, S.

Method I. 3-[2-(Aminosulfonyl)ethyl]-2-imino-6-trifluoromethoxy-benzothiazoline Hydrochloride (54). A solution of ethenesulfonyl fluoride28 (11.9 g, 0.108 mol) in DMF (10 mL) was added dropwise to a solution of 4-trifluoromethoxy-aniline (19.14 g, 0.108 mol) in 20 mL of DMF. The mixture was stirred at room temperature for 2 h, and the solution was poured into water (300 mL). The mixture was extracted with Et2O (3 × 100 mL), and the combined extracts were washed with water (2 × 100 mL) and then dried (MgSO4) and evaporated to lead to the sulfonyl fluoride 108 as an orange oil (25.8 g, 75%): 1H NMR δ (400 MHz, CDCl3) 3.57 (m, 2H, CH2SO2F), 3.77 (t, 2H, J ) 6.5 Hz, NCH2), 4.05 (very bb, 1H, NH), 6.56 (d, 2H, J ) 8.5 Hz, 3,5-ArH), 7.08 (d, 2H, J ) 8.5 Hz, 2,6-ArH). This sulfonyl fluoride (8.6 g, 0.03 mol) was dissolved in acetone (20 mL) and added dropwise to a refluxing mixture of 8 N NH4OH solution (30 mL, 8 molar equiv) and acetone (30 mL). After 1 h at the same temperature, the acetone was removed in vacuo and the mixture extracted with EtOAc (2 × 50 mL). The combined extracts were dried (MgSO4), filtered, and concentrated under vacuum. The residue obtained was purified by flash chromatography on silica gel, using 50% EtOAc/cyclohexane as eluent, to give the sulfonamide 109 (R ) NH2) as a colorless oil (5.45 g, 64%): 1H NMR δ (200 MHz, CDCl3) 3.37 (t, 2H, J ) 6.5 Hz, CH2SO2NH2), 3.63 (bm, 2H, NCH2), 4.39 (bb, 1H, NH), 5.16 (bb, 2H, SO2NH2), 6.58 (d, 2H, J ) 8.5 Hz, 3,5-ArH), 7.05 (bd, 2H, J ) 8.5 Hz, 2,6-ArH). This sulfonamide (4.12 g, 0.0144 mol) was dissolved in acetic acid (20 mL) at room temperature. KSCN (5.6 g, 0.0577 mol) was added all at once, and then a solution of bromine (2.3 g, 0.0144 mol) in acetic acid (10 mL) was added dropwise (15 min). The reaction mixture was stirred overnight at room temperature, then diluted with water (30 mL), and treated with 30% NaOH. The orange precipitate was filtered and then washed with methanol. The methanolic solution was concentrated to dryness and the solid residue solubilized in EtOH/ Et2O and treated with HCl in Et2O (3.6 mL of 4.2 N solution) to give the expected sulfonamide 54 as a colorless solid (2.9 g, 53%): mp 225 °C (sublimes); 1H NMR δ (200 MHz, DMSO-d6) 3.61 (bt, 2H, J ) 6 Hz, CH2SO2NH2), 4.81 (bt, 2H, J ) 6 Hz, NCH2), 7.39 (bb, 2H, NH2), 7.63 (bd, 1H, J ) 8.5 Hz, 5-H), 7.81 (d, 1H, J ) 8.5 Hz, 4-H), 8.21 (bs, 1H, 7-H), 11.00 (2bb, 2H, dNH‚HCl); MS m/e 341 (M+), 234 (100). Anal. (C10H10F3N3O3S2.HCl) C: calcd, 31.79; found, 31.30; H, Cl, F, N, S. Compounds 55 and 56 were prepared from 108 as described for 54, using the appropriate amine. 2-Imino-3-[2-(methylaminosulfonyl)ethyl]-6-trifluoromethoxy-benzothiazoline Hydrochloride (55): mp 242 °C; 1H NMR δ (400 MHz, DMSO-d ) 2.64 (d, 3H, J ) 5 Hz, SO 6 2 NHCH3), 3.62 (t, 2H, J ) 6.5 Hz, CH2SO2, 4.74 (t, 2H, J ) 6.5 Hz, NCH2), 7.53 (q, 1H, J ) 5 HZ, SO2NHCH3), 7.63 (bd, 1H, J ) 8.5 Hz, 5-H), 7.75 (d, 1H, J ) 8.5 Hz, 4-H), 8.17 (bs, 1H, 7-H); MS m/e 355 (M+), 234 (100). Anal. (C11H12F3N3O3S2‚HCl) C, H, Cl, F, N, S. 3-[2-(Dimethylaminosulfonyl)ethyl]-2-imino-6-trifluoromethoxy-benzothiazoline (56): mp 140 °C; 1H NMR δ (200 MHz, DMSO-d6) 2.81 (s, 6H, SO2N(CH3)2), 3.43 (t, 2H, J ) 7 Hz, CH2SO2NMe2), 4.28 (t, 2H, J ) 7 Hz, NCH2), 7. 11 (d, 1H, J ) 8.5 Hz, 4-H), 7.27 (bd, 1H, J ) 8.5 Hz, 5-H), 7.61 (bs, 1H, 7-H), 8.61 (s, 1H, dNH); MS m/e 369 (M+), 234 (100). Anal. (C12H14F3N3O3S2) C, H, F, N, S. 2-(2-Imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanesulfonic Acid (57), The sulfonyl fluoride 108 (7.0 g, 0.024 mol) was dissolved in glacial acetic acid (30 mL) and heated under reflux for 40 h. After the mixture cooled, the colorless needles were filtered, washed with water, and dried to give the expected sulfonic acid 109 (R ) OH) (2.0 g, 29%): mp 220 °C; 1H NMR δ (400 MHz, DMSO-d6) 2.85 (t, 2H, CH2SO3), 3.50 (t, 2H, CH2N), 7.3 (d, 2H, J ) 8 Hz, ArH), 7.4 (d, 2H, J ) 8 Hz, ArH), 9.3 (bs, NH + SO3H + H2O); MS m/e 285 (M+), 190 (100). This sulfonic acid (1.8 g, 0.0063 mol) was dissolved in glacial acetic acid (20 mL). KSCN (2.46 g, 0.025 mol) was added all at once to this solution, followed by a dropwise addition of a

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solution of bromine (1.0 g, 0.0063 mol) in acetic acid (10 mL). The mixture was then stirred overnight at room temperature, then diluted with water (30 mL) and treated with 30% NaOH. After acidification with 1 N HCl, the precipitate was filtered, washed with water, and dried. Recrystallization in methanol gave the expected benzothiazoline sulfonic acid 57 as a yellow powder (1.05 g, 49%): mp >260 °C; 1H NMR δ (200 MHz, DMSO-d6) 2.97 (bt, 2H, J ) 6 Hz, NCH2CH2SO3H), 4.51 (bt, 2H, J ) 6 Hz, NCH2CH2SO3H), 7.61 (bd, 1H, J ) 8.5 Hz, 5-H), 7.80 (d, 1H, J ) 8.5 Hz, 4-H), 8.11 (bs, 1H, 7-H), 10.20 (bb, 2H, dNH‚HCl); MS m/e (CI+) 360 (M + NH4+), 343 (M + 1+). Anal. (C10H9F3N2O4S2) C: calcd, 35.09; found, 34.5; H, F, N, S. (2-Imino-6-trifluoromethoxy-3-benzothiazolinyl)acetic Acid (51). A stirred solution of 2-imino-3-methoxycarbonylmethyl-6-trifluoromethoxy-benzothiazoline 50 (10.19 g, 0.026 mol) in 6 N HCl (40 mL) was heated to reflux for 20 h. The reaction mixture was cooled to room temperature and the precipitate filtered and washed with water. Treatment of this solid with 1 N NaOH (60 mL), followed by recrystallization in water (25 mL), yielded the sodium salt of the expected compound 51 as a colorless solid (3.12 g, 28%): mp >260 °C; 1H NMR δ (200 MHz, DMSO-d ) 4.30 (bs, 2H, NCH CO Na), 6 2 2 6.83 (dd, 1H, J ) 8.5 Hz, J′) 2 Hz, 4-H), 7.18 (bd, 1H, J ) 8.5 Hz, 5-H), 7.54 (bs, 1H, 7-H); MS m/e 234 (M - CH2CO2Na + 1+), 219 (100). Anal. (C10H6F3N2NaO3S) C, H, F, N, S. 2-Imino-3-(2-mercaptoethyl)-6-trifluoromethoxy-benzothiazoline Hydrobromide (66). The intermediate 2-imino3-(2-tert-butylthioethyl)-6-trifluoromethoxy-benzothiazoline 110 (prepared following method F) was converted to 66 by a method similar to that described for 51 (using 48% HBr instead of 6 N HCl): yield 0.85 g (53%); mp 180 °C; 1H NMR δ (300 MHz, DMSO-d6) 2.85 (dd, 2H, J ) 8 Hz, J′ ) 7 Hz, NCH2CH2SH), 3.07 (t, 1H, J ) 8 Hz, NCH2CH2SH), 4.45(t, 2H, J ) 7 Hz, NCH2CH2SH), 7.60 (bd, 1H, J ) 8.5 Hz, 5-H), 7.96 (d, 1H, J ) 8.5 Hz, 4-H), 8.20(bs, 1H, 7-H), 10.45 (bb, 2H, dNH‚HBr); MS m/e 294 (M+), 234 (100). Anal. (C10H9F3N2OS2‚HBr) C, H, Br, F, N, S. 2-Imino-3-(2-methylaminoethyl)-6-trifluoromethoxybenzothiazoline Dihydrochloride (72). To a stirred solution of 2-imino-3-(2-dimethylaminoethyl)-6-trifluoromethoxybenzothiazoline 73 (2.7 g, 0.0088 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.35 g, 0.0088 mol) in CH2Cl2 at room temperature was added dropwise vinyl chloroformate (2.17 g, 0.020 mol), and the reaction mixture was allowed to stand overnight at the same temperature. The precipitate was then filtered and washed with CH2Cl2, and the filtrate was concentrated to dryness. The residue was purified by rapid filtration on silica gel leading to a yellow oil of the intermediate dicarbamate (1.1 g, 29%). After refluxing this compound with 37% HCl (2 mL) in methanol (10 mL) for 24 h, the reaction mixture was concentrated to dryness and the residue recrystallized in ethanol to give the dihydrochloride of the expected compound 72 as colorless crystals (0.31 g, 33%): mp 152 °C; 1H NMR δ (300 MHz, DMSO-d6), 2.62 (s, 3H, NCH3), 3.4 (t, 2H, J ) 5 Hz, NCH2CH2NHMe), 4.78 (t, 2H, J ) 5 Hz, NCH2CH2NHMe), 7.6 (bd, 1H, 5-H), 8.08 (d, 1H, J ) 9 Hz, 4-H), 8.19 (bs, 1H, 7-H), 9.49 (m, 2H, NHR2‚HCl), 10.7-11.7 (m, 2H, dNH‚HCl); MS m/e (CI+) 292 (M + 1+). Anal. (C11H12F3N3OS‚2HCl) C, H, Cl, F, N, S. (RS)-2-Imino-3-(2-methylsulfinylethyl)-6-trifluoromethoxy-2-benzothiazoline (64): m-Chloroperbenzoic acid (60.5 g, 0.263 mol) was added progressively to a stirred solution of 3-(2-methylthioethyl)-6-trifluoromethoxy-2-benzothiazolimine 61 (81.3 g, 0.263 mol) in 900 mL of absolute ethanol at -35 °C. The reaction mixture was stirred for 30 min after the addition was completed and then poured into 3 L of Et2O. To this cold stirred solution, 65 mL of a 4 N Et2O‚HCl solution was added dropwise. The resulting white precipitate was filtered and purified by acid-base treatment to give 64 as hydrochloride (72.5 g, 70%): mp 186 °C; 1H NMR δ (200 MHz, DMSO-d6), 2.67 (s, 3H, S(O)CH3), 3.19 and 3.38 (two dt, 1H each, J ) 14 and 6.5 Hz, CH2S(O)Me), 4.76 (t, 2H, J ) 6.5 Hz,

NCH2CH2S(O)Me), 7.59 (bd, 1H, 5-H), 7.8 (d, 1H, J ) 9 Hz, 4-H), 8.13 (bs, 1H, 7H); MS m/e 324 (M+), 259 (100), 234 (95); Anal. (C11H11F3N2O2S2-1.0HCl‚0.79H2O) C, H, Cl, F, N, S: calcd, 17.77; found, 17.2. Compounds 60, 68, 70, and 84-87 could be obtained from the corresponding thioether following the same synthetic pathway. (RS)-2-Imino-3-methylsulfinylmethyl)-6-trifluoromethoxy-2-benzothiazoline Hydrochloride (60): mp 150 °C (sublimes); 1H NMR δ (200 MHz, DMSO-d6), 2.93 (s, 3H, S(O)CH3), 5.9 (m, 2H, NCH2S(O)Me), 7.63 (bd, 1H, 5-H), 7.98 (d, 1H, J ) 9 Hz, 4-H), 8.18 (bs, 1H, 7-H), 11.35 (m, 2H, d NH‚HCl); MS m/e 310 (M+), 247 (80); Anal. (C10H9F3N2O2S2‚ 1.0HCl) C, H, Cl, F, N, S. (RS)-2-Imino-3-(2-phenylsulfinylethyl)-6-trifluoromethoxy-2-benzothiazoline Hydrochloride (68): mp 210 °C; 1H NMR δ (200 MHz, DMSO-d6), 3.30 and 3.57 (two dt, 1H each, J ) 14 and 7.5 Hz, CH2S(O)Ph), 4.7 (t, 2H, J ) 7.5 Hz, NCH2CH2S(O)Ph), 7.4-7.8 (m, 7H, ArH, 4-H and 5-H), 8.12 (bs, 1H, 7-H), 10.5-11.5 (m, 2H, dNH‚HCl); MS m/e 386 (M+), 261 (100); Anal. (C16H13F3N2O2S2‚1.0HCl‚0.48H2O) C, H, Cl, F, N, S. (RS)-2-Imino-3-(3-methylsulfinylpropyl)-6-trifluoromethoxy-2-benzothiazoline (70): mp 114 °C; 1H NMR δ (200 MHz, CDCl3), 2.27 (m, 2H, NCH2CH2CH2S(O)Me), 2.6 (s, 3H, S(O)CH3), 2.83 (m, 2H, CH2S (O)Me), 4.07 and 4.20 (two dt, 1H each, J ) 11 and 6 Hz, NCH2CH2CH2S(O)Me), 6.92 (d, 1H, J ) 9 Hz, 4-H), 7.11 (bd, 1H, 5-H), 7.17 (bs, 1H, 7-H); MS m/e 338 (M+), 234 (90), 220 (100); Anal. (C12H13F3N2O2S2) C, H, F, N, S. (RS)-2-Imino-3-(2-ethylsulfinylethyl)-6-tert-butyl-2-benzothiazoline (84). The corresponding thioether was obtained by reacting the 6-tert-butyl-2-benzothiazolamine 22 with 2-chloroethyl-ethyl-sulfide, following method F: mp 100 °C; 1H NMR δ (200 MHz, DMSO-d ), 1.20 (t, 3H, J ) 6.5 Hz, 6 SCH2CH3), 1.30 (s, 9H, C(CH3)3), 2.60-3.30 (m, 4H, CH2SOCH2CH3), 4.25 (t, 2H, J ) 7 Hz, NCH2CH2SOEt), 7.05 (d, 1H, J ) 8.5 Hz, 4-H), 7.27 (dd, 1H, J ) 8.5 Hz, J′) 1 Hz, 5-H), 7.50 (d, 1H, J ) 1 Hz, 7-H), 8.18 (bb, 1H, dNH); MS m/e 311 (M + 1+), 231 (100). Anal. (C12H13F3N2O2S2) C, H, F, N, S. (RS)-2-Imino-3-(2-ethylsulfinylethyl)-6-n-butyl-2-benzothiazoline Hydrochloride (86). The corresponding thioether was obtained by reacting the 6-n-butyl-2-benzothiazolamine 21 with 2-chloroethyl-ethyl-sulfide, following method F: mp 174 °C; 1H NMR δ (200 MHz, DMSO-d6), 0.90 (t, 3H, J ) 7 Hz, butyl-CH3), 1.20 (t, 3H, J ) 7.5 Hz, SCH2CH3), 1.32 (m, 2H, butyl-CH2CH3), 1.58 (m, 2H, butyl-CH2CH2CH3), 2.68 (t, 2H, J ) 7 Hz, butyl-CH2CH2CH2CH3), 2.70-3.05 (m, 2H, SOCH2CH3), 3.15 and 3.35 (two dt, 1H each, J ) 14 and 6.5 Hz, NCH2CH2SOEt), 4.75 (t, 2H, J ) 6.5 Hz, NCH2CH2SOEt), 7.40 (bd, 1H, J ) 8.5 Hz, 5-H), 7.60 (d, 1H, J ) 8.5 Hz, 4-H), 7.82 (bs, 1H, 7-H), 10.88 (bb, 2H, dNH‚HCl); MS m/e 310 (M+), 231 (100). Anal. (C15H22N2OS2‚1.0HCl) C, H, Cl, N, O, S. (RS)-2-Imino-3-(2-ethylsulfinylethyl)-6-trifluoromethoxy-2-benzothiazoline Hydrochloride (86). The starting thioether was obtained by reacting 6-trifluoromethoxy-2benzothiazolamine with 2-chloroethyl-ethyl-sulfide, following method F: mp 174 °C; 1H NMR δ (200 MHz, DMSO-d6), 1.20 (t, 3H, J ) 7.5 Hz, SCH2CH3), 2.60-3.05 (m, 2H, SOCH2CH3), 3.15 and 3.35 (two dt, 2H, J ) 14 and 6.5 Hz, NCH2CH2SOEt), 4.80 (t, 2H, J ) 6.5 Hz, NCH2CH2SOEt), 7.62 (bd, 1H, J ) 8.5 Hz, 5-H), 7.80 (d, 1H, J ) 8.5 Hz, 4-H), 8.20 (bs, 1H, 7-H), 10.5-11.80 (two very bb, 2H, dNH‚HCl); MS m/e 338 (M+), 234 (100). Anal. (C12H13F3N2O2S2‚1.0HCl‚0.8H2O) C, H, Cl, F, N, S. (RS)-2-Imino-3-(2-ethylsulfinylethyl)-6-trifluoromethyl2-benzothiazoline Hydrochloride (87). The starting thioether was obtained by reacting the 6-trifluoromethyl-2benzothiazolamine 37 with 2-chloroethyl-ethyl-sulfide, following method F: mp 150 °C; 1H NMR δ (200 MHz, DMSO-d6), 1.17 (t, 3H, J ) 7.5 Hz, SCH2CH3), 2.65-3.00 (m, 2H, SOCH2CH3), 3.15 and 3.35 (two dt, 2H, J ) 14 and 6.5 Hz, NCH2CH2SOEt), 4.82 (t, 2H, J ) 6.5 Hz, NCH2CH2SOEt), 7.94 (limit AB, 2H, J ) 8.5 Hz, 4-H and 5-H), 8.50 (bs, 1H, 7-H), 11.20 (very bb,

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2H, dNH‚HCl); MS m/e 322 (M+), 218 (100). Anal. (C12H13F3N2OS2‚1.0HCl) C, H, Cl, F, N, S. 2-Imino-3-(2-methylsulfonylethyl)-6-trifluoromethoxybenzothiazoline Hydrochloride (65). m-Chloroperbenzoic acid (26.9 g, 0.117 mol) was added to a stirred solution of 2-imino-3-(2-methylthioethyl)-6-trifluoromethoxy-benzothiazoline 61 (17.8 g, 0.0577 mol) in 400 mL of CH2Cl2 at room temperature. The reaction was allowed to continue overnight at room temperature, and then the mixture was poured into 200 mL of Et2O. The hydrochloride was precipitated by addition of 4 N Et2O‚HCl and the resulting solid recrystallized in water to give 65 (17.4 g, 80%): mp >260 °C; 1H NMR δ (200 MHz, DMSO-d6), 3.21 (s, 3H, SO2CH3), 3.75 (t, 2H, J ) 6.5 Hz, NCH2CH2SO2Me), 4.83 (t, 2H, J ) 6.5 Hz, NCH2CH2SO2Me), 7.65 (bd, 1H, 5-H), 7.76 (d, 1H, J ) 9 Hz, 4-H), 8.2 (bs, 1H, 7-H), 10.5-11.5 (m, 2H, dNH‚HCl); MS m/e 340 (M+), 234 (100), 165 (30); Anal. (C11H11F3N2O3S2‚1.0HCl) C, H, Cl, F, N, S. Compounds 71, 88, and 89, starting from the corresponding thioether 69, 120, and 121, respectively, were prepared following the same synthetic pathway. 2-Imino-3-(3-methylsulfonylpropyl)-6-trifluoromethoxybenzothiazoline Oxalate (71): mp 180 °C; 1H NMR δ (200 MHz, DMSO-d6), 2.1 (m, 2H, NCH2CH2CH2SO2Me), 3.0 (s, 3H, SO2CH3), 3.28 (m, 2H, NCH2CH2CH2SO2Me), 4.21 (t, 2H, J ) 7 Hz, NCH2CH2CH2SO2Me), 7.46 (bd, 1H, 5-H), 7.56 (d, 1H, J ) 9 Hz, 4-H), 7.9 (bs, 1H, 7-H); MS m/e 354 (M+), 275 (100), 248 (60), 234 (100),165 (40); Anal. (C12H13F3N2O3S2, C2H2O4) C, H, F, N, S. 3-(2-Ethylsulfonylethyl)-2-imino-6-pentafluoroethylbenzothiazoline (88): mp 125 °C; 1H NMR δ (400 MHz, CDCl3), 1.40 (t, 3H, J ) 7 Hz, SO2CH2CH3), 3.03 (q, 2H, J ) 7 Hz, SO2CH2CH3), 3.45 (t, 2H, J ) 7.5 Hz, NCH2CH2SO2Et), 4.43 (t, 2H, J ) 7.5 Hz, NCH2CH2SO2Et), 7.15 (d, 1H, J ) 8 Hz, 4-H), 7.46 (s, 1H, 7-H), 7.48 (d, 1H, J ) 8 Hz, 5-H); MS m/e 388 (M+), 199 (100). Anal. (C13H13F5N2O2S2) C, H, F, N, S. The starting 3-(2-ethylthioethyl)-2-imino-6-pentafluoroethylbenzothiazoline (120) was prepared following method F starting from the 6-pentafluoroethyl-2-benzothiazolamine 36: mp < 50 °C; 1H NMR δ (400 MHz, CDCl3) 1.30 (t, 3H, J ) 7.5 Hz, SCH2CH3), 2.65 (q, 2H, J ) 7.5 Hz, SCH2CH3), 2.90 (dd, 2H, J ) 7 Hz, NCH2CH2S), 4.17 (dd, 2H, J ) 7 Hz, NCH2CH2S), 7.00 (d, 1H, J ) 8 Hz, 4-H), 7.20 (bb, 1H, dNH), 7.46 (bd + s, 2H, 5-H + 7-H). 3-(2-Ethylsulfonylethyl)-2-imino-6-pentafluoroethoxybenzothiazoline Hydrochloride (89): mp 230 °C; 1H NMR δ (200 MHz, DMSO-d6), 1.24 (t, 3H, J ) 7.5 Hz, SO2CH2CH3), 3.30 (q, 2H, J ) 7.5 Hz, SO2CH2CH3), 3.72 (t, 2H, J ) 7 Hz, NCH2CH2SO2Et), 4.78 (t, 2H, J ) 7 Hz, NCH2CH2SO2Et), 7.62 (bd, 1H, J ) 8.5 Hz, 5-H), 7.74 (d, 1H, J ) 8.5 Hz, 4-H), 8.16 (bs, 1H, 7-H), 11.90 (very bb, 2H, dNH‚HCl); MS m/e 404 (M+), 165 (100). Anal. (C13H13F5N2O3S2‚1.0HCl) C, H, Cl, F, N, S. The starting 3-(2-ethylthioethyl)-2-imino-6-pentafluoroethoxy-benzothiazoline hydrochloride (121) was prepared following method F starting from the 6-pentafluoroethoxy-2benzothiazolamine 35: mp 115 °C; 1H NMR δ (200 MHz, DMSO-d6) 1.14 (t, J ) 7.5 Hz, 3H, SCH2CH3), 2.64 (q, J ) 7.5 Hz, 2H, SCH2CH3), 2.94 (bt, J ) 7 Hz, 2H, NCH2CH2S), 4.58 (bt, J ) 7 Hz, 2H, NCH2CH2S), 7.57 (bd, 9 Hz, 1H, 5-H), 7.83 (d, J ) 9 Hz, 1H, 4-H), 8.17 (bs, 1H, 7-H), 1 1.0 (bb, 2H, dNH2 + Cl-). 3-(2-Ethylthioethyl)-2-methylimino-6-trifluoromethoxybenzothiazoline Hydrochloride (90). (a) 2-Chloro-6-trifluoromethoxy-benzothiazole55 (22.05 g, 0.087 mol) and a 40% aqueous solution of methylamine were shaken at 110 °C in a sealed pressure flask. After 24 h the mixture was poured into distilled water (300 mL), and the precipitate was collected by filtration, washed with water, and dried to give 2-methylamino-6-trifluoromethoxy-benzothiazole 113 as a white solid (19.52 g, 90.4%): mp 168 °C; 1H NMR δ (200 MHz, DMSO-d6) 2.96 (dt, 3H, NHCH3), 7.20 (dd, 1H, J ) 9 and 2 Hz, 5-H), 7.45 (d, 1H, J ) 9 Hz, 4-H), 7.80 (m, 1H, 7-H), 8.1 (bq, 0.7H, J ) 5 Hz, NHMe); Anal. (C9H7F3N2OS) C, H, F, N, S.

(b) This compound (7.05 g, 0.0284 mol) and 2-chloroethylethyl-sulfide were dissolved in 2-butanone and heated under reflux for 48 h. The reaction mixture was then cooled to room temperature, and the precipitate was collected by filtration, washed with the same solvent, and recrystallized from 2-propanol to give 90 as a colorless powder (5.33 g, 50.3%): mp 150 °C (sublimes); 1H NMR δ (250 MHz, DMSO-d6) 1.14 (t, 3H, J ) 7.5 Hz, SCH2CH3), 2.65 (q, 2H, J ) 7.5 Hz, SCH2CH3), 2.93 (t, 2H, J ) 7 Hz, NCH2CH2SEt), 3.14 (s, 3H, dNCH3), 4.67 (t, 2H, J ) 7 Hz, NCH2CH2SEt), 7.63 (bd, 1H, J ) 8.5 Hz, 5-H), 7.82 (d, 1H, J ) 8.5 Hz, 4-H), 8.28 (bs, 1H, 7-H), 9.00-11.50 (very bb, 1H, dNMe‚HCl); MS m/e 336 (M+), 248 (100). Anal. (C13H15F3N2OS2‚l.0HCl) C, H, Cl, F, N, S. 2-Ethylimino-3-(2-methylthioethyl)-6-trifluoromethoxybenzothiazoline Hydrochloride (91). Compound 91 was preprared in the same way as described for 90 using ethylamine in the first step to obtain the 2-(ethylamino)-benzothiazole 114 and 2-chloroethyl-methyl-sulfide in the second step: mp 208 °C (sublimes); 1H NMR δ (200 MHz, DMSO-d6) 1.35 (t, 3H, J ) 7.5 Hz, dNCH2CH3), 2.18 (s, 3H, SCH3), 2.90 (t, 2H, J ) 7 Hz, NCH2CH2SMe), 3.55 (q, 2H, J ) 7.5 Hz, dNCH2CH3), 4.75 (t, 2H, J ) 7 Hz, NCH2CH2SEt), 7.60 (bd, 1H, J ) 8.5 Hz, 5-H), 7.83 (d, 1H, J ) 8.5 Hz, 4-H), 8.28 (bs, 1H, 7-H), 11.65 (bb, 1H, dNEt‚HCl); MS m/e 336 (M+), 262 (100). Anal. (C13H15F3N2OS2‚1.0HCl) C, H, Cl, F, N, S. 3-(2-Ethylthioethyl)-2-methoxyimino-6-trifluoromethoxy-benzothiazoline (92): (a) To a solution of thiourea (12 g, 0.157 mol) in 1 N sulfuric acid (200 mL) was added the 2-chloro derivative 112 (25.4 g, 0.1 mol), and the yellow suspension was heated to 60 °C. After 25 h the mixture was cooled to room temperature, and the precipitate was collected by filtration, washed with water and petroleum ether, and dried to give the thiol 115 as a colorless solid (22.7 g, 90.3%): mp 228 °C; 1H NMR δ (250 MHz, DMSO-d6) 7.35 and 7.42 (limit AB, 1H each, J ) 8.5 Hz, 4-H and 5-H, respectively), 7.87 (bs, 1H, 7-H), 13.5-14.3 (very bb, 1H, NdC-SH); MS m/e 251 (M+), 69 (100). (b) This thiol (22.4 g, 0.089 mol) was dissolved in DMF (90 mL) and added to a stirred and hot (100 °C) solution of 1,2dibromoethane (163 g, 0.86 mol) in DMF (90 mL). After 19 h at the same temperature the mixture was cooled to 0 °C, and the white precipitate was collected and recrystallized from a 95% aqueous solution of EtOH (450 mL) to give the tricyclic thiazolium salt 116 (18.37 g, 57.6%): mp >260 °C; 1H NMR δ (200 MHz, DMSO-d6) 4.28 (t, 2H, J ) 7.5 Hz, dN+CH2CH2S), 5.02 (t, 2H, J ) 7.5 Hz, dN+CH2CH2S), 7.83 and 8.18 (two bd, 1H each, J ) 8.5 Hz, 4-H and 5-H), 8.50 (bs, 1H, 7-H); MS m/e 356 (M - 1+), 278 (100). Anal. (C10H7BrF3NOS2‚0.5H2O) C, H, Br, F, N, S. (c) This salt (3.6 g, 0.01 mol) was added to an aqueous solution (5 mL) of methoxylamine hydrochloride (2.5 g, 0.03 mol). This mixture was treated with 1 N NaOH (10 mL), heated under reflux for 20 min, and then cooled, filtered, and concentrated. The residue was added to water and extracted with Et2O (2 × 100 mL). The combined organic extracts were washed with water, dried (MgSO4), and evaporated to give the thiol oxime 117 as a colorless solid (1.23 g, 37.9%): mp 70 °C; 1H NMR δ (200 MHz, DMSO-d ), 2.66 (t, 1H, J ) 8 Hz, SH), 6 2.80 (dd, 2H, J ) 8 and 7 Hz, NCH2CH2SH), 3.80 (s, 3H, d NOCH3), 4.03 (t, 2H, J ) 7 Hz, NCH2CH2SH), 7.28 and 7.35 (limit AB, 2H, J ) 8.5 Hz, 5-H and 4-H, respectively), 7.72 (bs, 1H, 7-H); MS m/e 324 (M+), 233 (100). (d) To a solution of 117 (1.15 g, 0.0035 mol) in EtOH (5 mL) under an atmosphere of nitrogen was added sodium ethylate (prepared from 0.081 g of Na in 5 mL of EtOH) followed by ethyl bromide (0.77 g, 0.0071 mol). The resulting mixture was stirred at room temperature overnight then evaporated to dryness under vacuum, and the solid residue was washed with water and recrystallized from EtOH to give 92 as a colorless solid (0.56 g, 45.5%): mp 68 °C; 1H NMR δ (200 MHz, DMSOd6) 1.20 (t, 3H, J ) 7.5 Hz, SCH2CH3), 2.60 (q, 2H, J ) 7.5 Hz, SCH2CH3), 2.85 (t, 2H, J ) 7 Hz, NCH2CH2SEt), 3.78 (s, 3H, dNOCH3), 4.02 (t, 2H, J ) 7 Hz, NCH2CH2SEt), 7.25 (limit

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AB, 2H, 5-H and 4-H), 7.72 (bs, 1H, 7-H); MS m/e 352 (M+), 89 (100). Anal. (C13H15F3N2O2S2) C, H, F, N, S. 3-(2-Ethylthioethyl)-2-hydroxyimino-6-trifluoromethoxy-benzothiazoline (93). Compound 93 was prepared, as described above for 92, using hydroxylamine: mp 136 °C; 1 H NMR δ (200 MHz, DMSO-d6) 1.22 (t, 3H, J ) 7.5 Hz, SCH2CH3), 2.62 (q, 2H, J ) 7.5 Hz, SCH2CH3), 2.85 (t, 2H, J ) 7 Hz, NCH2CH2SEt), 4.05 (t, 2H, J ) 7 Hz, NCH2CH2SH), 7.22 (limit AB, 2H, J ) 8.5 Hz, 5-H and 4-H), 7.70 (bs, 1H, 7-H); MS m/e 338 (M+), 89 (100). Anal. (C12H13F3N2O2S2) C, H, F, N, S. 2-Acetylimino-3-(2-methylthioethyl)-6-trifluoromethoxy-benzothiazoline (94). Acetyl chloride (0.46 g, 0.0058 mol) was added dropwise to a stirred solution of 61 (1.34 g, 0.0039 mol) and triethylamine (0.79 g, 0.0078 mol) in acetone (15 mL), and the mixture was left at room temperature overnight. Water was then added, and the white precipitate was collected by filtration and recrystalized from refluxing methanol to give 94: mp 110 °C; 1H NMR δ (200 MHz, CDCl 3) 2.25 (s, 3H, SCH3), 2.35 (s, 3H, dNCOCH3), 2.95 (t, 2H, J ) 7.5 Hz, NCH2CH2SMe), 4.55 (t, 2H, J ) 7.5 Hz, NCH2CH2SMe), 7.32 (AB, 2H, 5-H and 4-H), 7.55 (bs, 1H, 7-H); MS m/e 350 (M+), 234 (100). Anal. (C13H13F3N2O2S2) C, H, F, N, S. 3-(2-Methylthioethyl)-6-trifluoromethoxy-2-benzothiazolone (95). The tricyclic thiazolium 116 (4.35 g, 0.012 mol) was added to a stirred methanolic solution (100 mL) of sodium methylate (prepared from 0.279 g of sodium) under an atmosphere of nitrogen. After refluxing for 23 h, the reaction mixture was evaporated to dryness under vacuum, and the residue was diluted with water (100 mL) and extracted with CH2Cl2 (2 × 50 mL). The combined organic extracts were washed with water, dried (MgSO4), and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 20% EtOAc in cyclohexane to give 95 as a yellow oil (1.13 g, 30.2%): 1H NMR δ (200 MHz, DMSO-d6) 2.13 (s, 3H, SCH3), 2.84 (t, 2H, J ) 6.5 Hz, NCH2CH2SMe), 4.15 (t, 2H, J ) 6.5 Hz, NCH2CH2SMe), 7.40 (bd, 1H, J ) 8.5 Hz, 5-H), 7.55 (d, IH, J ) 8.5 Hz, 4-H), 7.89 (bs, 1H, 7-H); MS m/e 309 (M+), 74 (100). Anal. (C11H10F3NO2S2) C, H, F, N, S. 2,3-Dihydro-9a-methylthio-7-trifluoromethoxy-thiazolo[2,3-b]benzothiazole (119). The tricyclic thiazolium 116 (4.35 g, 0.012 mol) was added to a stirred ethanolic solution (45 mL) of sodium methanethiolate (0.9 g, 0.012 mol). After 0.5 h at room temperature, the precipitate was removed and the filtrate evaporated to dryness. Recrystallization from ethanol gave 119 as a colorless solid (1.8 g, 46.1%): mp 86 °C; 1H NMR δ (200 MHz, DMSO-d6) 2.20 (s, 3H, SCH3), 2.90 and 3.20 (two m, 1H each, NCH2CH2S), 3.60 and 4.61 (two m, 1H each, NCH2CH2S), 7.13 (limit AB, 2H, J ) 8.5 Hz, 5-H and 4-H, respectively), 7.43 (bs, 1H, 7-H); MS m/e 325 (M+), 278 (100). Anal. (C11H10F3NOS3) C, H, F, N, S. Glutamic Acid-Induced Seizures.31 Groups of seven male Sprague-Dawley rats per dose weighing 200 ( 20 g were used. Drugs were injected i.p. at at least 3 concentrations (normally 1, 3, and 10 mg/kg) plus vehicle alone 30 min prior to intracerebroventricular (icv) administration of 10 µL/rat of a 12.5 µmol/kg solution of L-glutamic acid in saline according to a free hand technique. After this treatment, the rats were observed for 30 min; L-glutamic acid alone provoked seizures immediately after injection: animals ran wildly, jumped violently, and exhibited clonic seizures. ED50 for studied compounds was defined as the dose of drug (mg/kg) which totally protected 50% of the rats from clonic convulsions. In this test, riluzole (1) displayed an ED50 of 3.2 ( 0.6 mg/kg (19% variability). A similar variability was observed with the other evaluated compounds. The majority of compounds were tested once only. Mortality Induced by Hypobaric Hypoxia.37 Each mouse was enclosed in a 1 L decompression container. The animal was brought to a simulated altitude of 12 000 m at a speed of 70 m/s (maximum hypobaric pressure ) 200 hPa). The pressure was controlled by a numeric captor (Enertec/Schlumberger CA4300/0/1). After the simulated altitude was reached,

the survival time for each mouse was measured. With this material and protocol, two groups of six mice can be observed simultaneously. Under these conditions, the mean survival time for control mice was 230.4 ( 4.0 s. Each compound to be tested was given to six mice per dose (2.5 mL/100 g body weight) by intraperitoneal route (i.p.) 30 min before the challenge. In this test, riluzole (1) displayed an ED50 of 4.0 ( 0.8 mg/kg (20% variability). The same variability was observed with the other compounds evaluated, unless otherwise stated in Table 8 for compounds 65, 78, and 79. The authors thank C. Pauchet for some biological data, M. Vuilhorgne, Mrs. Foucault, and co-workers for structural data and elemental analyses, and C. Luttmann for ClogP calculations.

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JM980202U

Riluzole Series. Synthesis and in Vivo - American Chemical Society

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